Abstract
Current research into schizophrenia has remained highly fragmented, much like the clinical presentation of the disease itself. Differing theories as to the cause and progression of schizophrenia, as well as the heterogeneity of clinical symptoms, have made it difficult to develop a coherent framework suitable for animal modelling. However, a number of limited animal models have been developed to explore various causative theories and to test specific mechanistic hypotheses. Historically, these models have been based on the manipulation of neurotransmitter systems believed to be involved in schizophrenia. In recent years, the emphasis has shifted to targeting relevant brain regions in an attempt to explore potential etiologic hypotheses. The specific animal models developed within these frameworks are described in this review. Emphasis is placed on the critical evaluation of currently available models because these models help to shape the direction of future research.
Medical subject headings: brain; causality; developmental biology; dopamine; GABA; genetic predisposition to disease; genetics, biochemical; glutamic acid; disease models, animal; neural pathways; neuronal plasticity; pharmacology; psychopathology; schizophrenia; serotonin
Abstract
La recherche en cours sur la schizophrénie demeure très fragmentée, tout comme la manifestation clinique de la maladie même. Comme les théories sur la cause et l'évolution de la schizophrénie diffèrent et compte tenu de l'hétérogénéité des symptômes cliniques, il est difficile d'établir un cadre cohérent qui convient à une modélisation animale. On a toutefois mis au point des modèles animaux limités pour explorer diverses théories relatives aux causes et vérifier des hypothèses mécanistes précises. Sur le plan historique, ces modèles reposent sur la manipulation des systèmes neurotransmetteurs que l'on croit impliqués dans la schizophrénie. Depuis quelques années, on cherche plutôt à cibler des régions pertinentes du cerveau afin d'explorer des hypothèses étiologiques possibles. On décrit dans cette critique les modèles animaux précis mis au point dans le contexte de ces cadres. On met l'accent sur l'évaluation critique des modèles actuellement disponibles parce qu'ils aident à orienter la recherche future.
Introduction
Differing theories as to the origin and course of schizophrenia are as old as the clinical identification of the disorder itself. Indeed, Kraeplin's original description more than a century ago of “precocious dementia,” closely followed by Clouston's concept of “developmental insanity,” form the basis of the current neurodegenerative and neurodevelopmental theories of schizophrenia, respectively. Although extensively redefined, these fundamentally contrasting principles remain as hotly debated today as ever. The past several decades have also brought tremendous advances in neuropharmacology that have extended our understanding of schizophrenia at both a neurochemical and neuroanatomical level. However, despite the advent of sophisticated analysis and imaging tools, or perhaps even because of them, our ability to synthesize a coherent model of schizophrenia remains as elusive as ever. Although there have been several attempts in recent years to unite these divergent frameworks into a unified theory,1,2,3,4,5,6 much of the current research on schizophrenia remains highly fragmented.
The purpose of this article is to critically review many of the animal models of schizophrenia presently under investigation, as a prelude to further research. The scientific exploration of human disorders has necessitated the development of suitable, if limited, animal models. Psychiatric conditions are no different in this regard and remain perhaps the most heavily modelled of all human conditions.7 This may at first seem surprising, given the lack of convincing evidence that any animal, with the probable exception of nonhuman primates, suffers from an identifiable mental illness. However, the prevailing modern view of neuroscience,8 for which there is extensive experimental evidence, is that clinically relevant psychiatric conditions have at their source a primary dysfunction of neuronal systems. Given that disruptions in neuronal activity can affect both human and animal behaviour, animal models can be developed to test various predictive and causative theories that cannot be addressed in human studies. Particular emphasis has been placed on pharmacological models in this review because they have played a dominant role in focusing experimental research efforts in this field.
There are several potential difficulties associated with modelling schizophrenia in animals, including the standard caveat of faithfully reproducing what is generally perceived to be a cognitive disorder in less cognitively developed animals. More specifically, heterogeneity in clinical symptoms, course of the disorder and potential causative factors represent significant obstacles to model building. Patients typically experience a combination of symptoms, often divided into positive (e.g., hallucinations, delusions, thought disorganizations), negative (e.g., loss of motivation, affective blunting, alogia, social withdrawal) and cognitive (e.g., deficits in attention, memory and executive functions).9,10,11 Many patients with schizophrenia also experience a wide range of catatonic phenomena such as catalepsy, stereotypies, echopraxia and unusual posturing and mannerisms.11,12 Similarly, the course and outcome of schizophrenia are remarkably variable, with only a minority of patients following a chronic, deteriorating course,13,14,15,16 despite enduring symptoms or functional deficits in most patients.13,14 Finally, a variety of environmental and genetic susceptibility factors17,18,19 have been proposed as potential causative agents.
Accordingly, current animal models of schizophrenia are not intended to serve as the complete animal equivalent of the human disorder. Rather, they are often designed to test specific causative or mechanistic hypotheses regarding schizophrenia. The models can be validated on the basis of how well their performance in a given test predicts the performance of humans with schizophrenia and on whether the model provides a sound theoretical rationale. These characteristics are referred to as predictive and construct validity, respectively, and are quite variable in models of psychiatric disorders. How accurately an animal model reproduces the symptoms of a human condition, known as face validity, is clearly the most difficult to establish for schizophrenia. However, as will be discussed later, a variety of behavioural correlates in animals may serve as approximate markers for psychiatric disturbances in humans.
For the purposes of this review, we define “animal model” as an experimental manipulation that elicits behavioural or neurochemical changes that can be related to schizophrenia using the criteria for predictive, construct and face validity. Measures that are reliable indicators of schizophrenia in humans, such as altered prepulse inhibition of startle (PPI) and latent inhibition (LI), are therefore not considered animal models in their own right, although they have sometimes been referred to as such.20,21 Rather, we consider these to be important features in establishing the validity of animal models. For those seeking a more detailed discussion of the implications of recent models and the appropriateness of modelling schizophrenia in general, the reader is referred to the recent review by Lipska and Weinberger.6
Pharmacologic models
Pharmacologic animal models of schizophrenia are based on our current understanding of the alterations in various neurotransmitter systems. As such, these models generally have some degree of construct validity, although it is extremely limited given our poor understanding of the fundamental basis of thought and cognition. Also, as expected, these models suffer from limited face validity. In contrast, predictive validity, although somewhat variable, is often fairly good because most pharmacologic models involve the administration of drugs that induce or exacerbate schizophrenic symptoms in humans.22 Perhaps the best known pharmacologic model, which is based on the dopamine hypothesis of schizophrenia, involves amphetamine administration.23,24
Dopamine
The dopamine (DA) hypothesis of schizophrenia proposes that dysfunction in DA neurotransmission is the underlying cause of the symptoms of the disorder. Specifically, hyperactivity of mesolimbic dopaminergic neurons is suggested to produce the positive symptoms of schizophrenia such as psychosis.25,26 A hypodopaminergic state in the frontal-cortical terminal fields of mesocortical DA neurons has also been proposed to be the basis of negative symptoms.27
Mesolimbic dopaminergic hyperactivity in schizophrenia may be maintained by pre- or postsynaptic mechanisms. Evidence for presynaptic hyperactivity includes excess DA release in response to amphetamine28,29,30 and increased L-DOPA decarboxylase levels in schizophrenia.30 Further, amphetamine and related substances such as 3,4-methylenedioxymethamphetamine (MDMA) have been shown to produce psychotic symptoms in healthy subjects.31,32 In addition, many patients with schizophrenia experience an exacerbation of psychotic symptoms in response to psychostimulants such as amphetamine and methylphenidate at doses that are not psychotogenic to normal controls.33,34,35
Postsynaptically, an increased number of DA receptors or associated signal transduction elements could also result in heightened sensitivity to DA. Although initially classified into D1 and D2 receptors based on differing biochemical and pharmacological profiles,36 these DA receptors are now recognized as 2 distinct receptor families.37,38,39 All typical antipsychotics are D2 receptor antagonists, and there is a strong correlation between clinical efficacy (i.e., antipsychotic effect) and the degree of D2 receptor antagonism.40,41,42 Similarly, D2 receptor density, as measured in post-mortem tissue and more recently in in vivo brain imaging studies, has been reported to be increased in schizophrenia.30,43,44,45 However, the effects of long-term antipsychotic treatment on D2 receptors is a common confound in many of the earlier studies.42 Changes in other DA receptors have also been reported in schizophrenia,46,47,48 but many of these studies suffer from similar limitations.49,50
In animal studies, the administration of amphetamine and related psychostimulants reliably stimulates behavioural alterations such as hyperlocomotion and stereotypy.23,51 Although the relevance of these motor disturbances to those shown by patients with schizophrenia is debatable, their reliable expression allows for a comparison among animal models. Moreover, amphetamine-induced stereotypic behaviour can be attenuated by treatment with antipsychotics,52 further supporting the validity of this model.
The face validity of dopaminergic animal models is also supported by the disruptive effects of DA receptor agonists on PPI.20,53 PPI is a test of preattentional sensorimotor gating, which is impaired in schizophrenia.54,55,56 Stimulus-evoked changes in PPI are similar in humans and rats, and the DA agonist apomorphine can disrupt PPI in both species, mimicking the PPI deficits observed in patients with schizophrenia.53 The administration of antipsychotic drugs can restore PPI function in rats treated with apomorphine, and this response has been correlated with both clinical antipsychotic potency and D2 receptor affinity. Interestingly, the atypical antipsychotic clozapine can also restore PPI in apomorphine-treated rats.53 Although the mechanism of action of clozapine in this regard is unclear, it does not appear to support a direct D2-receptor-mediated effect as with apomorphine on PPI. Finally, PPI can be disrupted in rats by the direct infusion of DA into the nucleus accumbens (NAC), an effect which can be also blocked by antipsychotics,53 thus supporting some degree of both predictive and construct validity for this model.
Despite the longevity of the DA hypothesis and its general usefulness in framing research on schizophrenia, the underlying mechanism by which DA activity is believed to be altered remains unknown. Indeed, there is relatively little direct evidence that DA plays a primary causal role in the development of the disorder.6,57,58,59 Also, some patients with schizophrenia, particularly those with predominantly negative symptoms, respond poorly or not at all to treatment with DA antagonists.60 Accordingly, despite the emphasis placed on this model in the literature, the construct validity of DA animal models of schizophrenia remains limited.
Glutamate
Nonparanoid schizophrenia, especially when it includes negative symptoms, can perhaps be mimicked more faithfully by the administration of phencyclidine (PCP),61,62 which appears to act predominantly on glutamatergic N-methyl-D-aspartate (NMDA) receptors.63 PCP and other NMDA receptor antagonists induce schizophrenic-like symptoms in healthy subjects and precipitate psychoses in patients with schizophrenia who have stabilized.64,65,66,67,68,69,70 This has led to the suggestion that schizophrenia may involve hypofunction of NMDA receptors.64,71,72,73
Long-term potentiation is disrupted by NMDA antagonists,74,75 and Kornhuber and colleagues76 reported increased binding to NMDA receptors in post-mortem frontal cortex of patients with schizophrenia.76 Similarly, a decreased release of glutamate has been reported in the frontal and temporal cortices of patients with schizophrenia,77 as have higher blood concentrations of glycine, glutamate and serine.78 Reduced expression of non-NMDA glutamate receptor subtypes in the medial temporal lobe of patients has also been reported.79,80,81
Glutamate may also be involved in schizophrenia through its interactions with DA,82 subtle forms of excitotoxicity73 or the developmental abnormality of corticocortical connections.83 Repeated exposure to PCP has been reported to reduce both basal and evoked DA utilization in the monkey prefrontal cortex (PFC), an effect which persisted even after PCP treatment was stopped.84 Taken together, these findings implicate altered glutamate neurotransmission and NMDA receptor function, in particular, in the negative and cognitive deficits observed in schizophrenia.
As in the case of DA receptor agonists, PCP administration can disrupt PPI and startle habituation in rats.20,85,86 Further, PCP and PCP-like drugs have also been shown to disrupt rat performance in the Morris water maze, 2-level alternation task and Y-maze brightness discrimination task.87 Altered social interactions have also been reported after treatments with PCP.88,89 Moreover, PCP produces amphetamine-like effects in rodents, including increased locomotor activity, stereotyped movements, circling and ataxia,64,87 and these effects are attenuated by antipsychotics and 6-hydroxydopamine lesions of the mesolimbic DA system.90,91 Repeated administration of PCP in monkeys also causes deficits in PFC-dependent tasks that can be ameliorated by the atypical antipsychotic clozapine.84 Taken together, these findings clearly support claims of face and predictive validity for this model, although construct validity remains difficult to ascertain, as with many current models of schizophrenia. Nevertheless, the glutamatergic basis of schizophrenia features prominently in many theories on the pathogenesis of this disorder, and the psychotropic effects of many neuroactive agents are believed to involve direct effects on this system.
An important aspect of NMDA antagonist animal models is that many of the studies to date have involved single injections. The relevance of this mode of administration to the hypothesized persistent disruptions of glutamatergic systems in schizophrenia remains unclear.
In contrast, long-term PCP administration has been reported to produce differential electrophysiological and neurochemical effects compared with single injections.84,92,93 Behaviourally, in monkeys, subchronic PCP treatment (i.e., twice a day for 14 days) produces performance deficits on a task involving PFC function,84 and continuous treatment has also been associated with a decrease in stereotyped locomotion and an increase in scanning behaviours.94 Behavioural tolerance to long-term PCP administration has also been reported for a trained response task in monkeys,95 and in rats, repeated PCP injections increase immobility time in the forced swim test, a feature associated with depressive symptoms.93,96 Differential effects of short- and long-term administration of PCP have also been shown on behavioural measures in the neonatal ventral hippocampus lesioned rat model of schizophrenia.93 For a more detailed overview of NMDA receptor models of schizophrenia, see Jentsch and Roth.97
Serotonin
The serotoninergic (5-HT) system has also been frequently implicated in schizophrenia.22 The 2 major classes of psychedelic hallucinogenic drugs, the indoleamines (e.g., lysergic acid diethylamide [LSD]) and phenethylamines (e.g., mescaline),98,99,100 are believed to mediate their effects through 5-HT2A receptors.101 Polymorphisms of the 5-HT2A receptor gene are reported to be a minor risk factor for schizophrenia.102 A loss of PFC 5-HT2A receptors along with an accompanying increase in 5-HT1A receptors103,104 and a blunted neuroendocrine response to 5-HT2A agonists105 have been reported in schizophrenia. However, recent positron emission tomography studies have been somewhat equivocal in regard to 5-HT2A receptor changes in schizophrenia (for example, see Trichard et al106). Nevertheless, the relatively high affinity of atypical antipsychotics such as clozapine for the 5-HT2A receptor supports a role of 5-HT systems in schizophrenia.107,108
As in the case with dopaminergic and glutamatergic animal models, LSD has been shown to disrupt startle habituation and PPI in humans and rats.109 Further, this effect is believed to be mediated through direct stimulation of 5-HT2A receptors.110 Indeed, the disruptive effects of PCP on PPI have also been proposed to be mediated through indirect activation of 5-HT2A receptors.86 Interestingly, both LSD and mescaline have been shown to enhance glutamatergic transmission in rats.86 5-HT3 receptor antagonists have also been shown to attenuate the behavioural hyperactivity caused by PCP,111 as well as amphetamine administration,112 but 5-HT3 receptor binding sites are not altered in schizophrenia,113 and the efficacy of 5-HT3 antagonists in clinical trials of schizophrenia has been variable.114,115,116
Despite evidence for altered serotonergic markers in schizophrenia, there is comparatively little evidence of a primary dysfunction of serotonergic systems in this disorder. Moreover, the relevance of LSD administration in animal models is unclear; repeated administration of LSD in humans or animals leads to behavioural tolerance, unlike the situation in schizophrenia.117 Thus, despite some support for face and predictive validity in this model, construct validity remains as difficult to establish as in the DA and glutamate animal models.
GABA
Alterations in γ-aminobutyric acid (GABA) neurotransmission in the PFC of patients have also been proposed, on the basis of both theory and experimental evidence.118,119,120,121 An interaction between dopaminergic and GABAergic systems in schizophrenia is supported by the fact that GABA neurons in the middle layers of PFC receive direct synaptic input from DA terminals, exert inhibitory control over excitatory output of layer III pyramidal neurons and undergo substantial developmental changes in late adolescence, the typical age of onset for schizophrenia.119,120,122 Evidence for reduced GABA uptake sites in the temporal lobe,123 increased GABAA receptor binding in superficial layers of cingulate cortex124 and reduced gene expression for glutamic acid decarboxylase in the prefrontal cortex125,126 provides direct support for GABAergic involvement in this disorder.
In animal studies, the GABAA receptor antagonist picrotoxin has been shown to reduce PPI in rats when injected into the medial PFC.118 Further, pretreatment with the DA antagonist haloperidol antagonized this effect, suggesting that blockade of GABA receptors in PFC impairs sensorimotor gating in a DA-dependent manner. However, the lack of any other reported GABA-induced behavioural deficits related to schizophrenic symptoms makes the face and predictive validity of this model difficult to establish. Further studies are required to establish the relevance of GABA-based pharmacological models of schizophrenia.
Lesion models
There has been considerable debate over the years about whether schizophrenia could be considered a neurodegenerative or neurodevelopmental disorder.127,128,129,130 The clinical deterioration that occurs in some cases suggests that neurodegenerative processes may be involved.71,130,131,132,133,134,135,136 Similarly, enlarged ventricles and decreased cortical volume may reflect an ongoing neurodegenerative process, but ventricular size does not seem to correlate with the duration of illness137 and appears to be present at the onset of symptoms, if not earlier. Moreover, this hypothesis suffers from both a lack of data supporting adult onset of pathologic cerebral changes and a lack of evidence of gliosis.50 Proliferation of glial cells is seen in most neurodegenerative conditions, and the absence of gliosis suggests that neuropathologic events occurred before the responsivity of glial cells to injury (i.e., before the third trimester of gestation).138 However, caution should be exercised in overinterpreting the lack of data supporting gliosis because the link between this injury marker and neurodegeneration remains unclear.
The neurodevelopmental theory of schizophrenia122,139,140 postulates that the pathogenic conditions leading to schizophrenia occur in the middle stage of intrauterine life, long before the formal onset of symptoms.140,141,142,143,144,145,146 Damage before this time would affect neurogenesis and thus lead to severe structural and cellular cortical abnormalities, which are not observed in schizophrenia.138 Further support for the theory is provided by reports of minor physical anomalies, based on the assumption that pre- or perinatal pathologic events may also lead to more visible physical abnormalities. Abnormal limb length and angle, fingerprint patterns and ridge counts and webbed digits have been reported in schizophrenia.147 Some studies also suggest the existence of premorbid neurologic abnormalities such as motor function and attention.148,149
Some animal models of schizophrenia, based on the concept of pre- or perinatal insults, suggest that various obstetric complications150,151,152,153,154,155 (e.g., genetic, ischemic, hemorrhagic, infectious agents) could result in abnormalities in pruning, cell death and developmental connectivity.139,156 However, such injuries are typically characterized by gliosis141 and are difficult to reconcile with the cytoarchitectural changes seen in schizophrenia. The nature of delivery complications also varies considerably between studies, making comparisons difficult.157 Nevertheless, studies of cesarean delivery and perinatal hypoxia or anoxia in rats have shown increased dopaminergic hyper-responsivity to psychostimulants154,158,159,160 and stress.161,162 Further, the effect has been shown to depend on the genetic background of the animal.163 Although these models provide some degree of validity, further research is required to determine the potential mechanism(s) of action of obstetric complications in schizophrenia.
To address some of the issues surrounding progressive neurodevelopmental or neurodegenerative changes in schizophrenia, a number of targeted lesion animal models have been developed. Although these can take the form of electrolytic or aspiration lesions, they more typically involve excitotoxic agents, which destroy neuronal tissue through stimulation of excitatory glutamate release or by acting as direct glutamate receptor agonists.
Given the evidence for the involvement of the PFC in schizophrenia, it is not surprising that this region has drawn a lot of interest in lesion studies. The PFC is involved in higher cognitive functions such as attention, working memory, emotional expression and social interaction.164,165 Hypofunction of dopaminergic projections at the level of the dorsolateral PFC, in particular, has been implicated in the metabolic hypofrontality seen in patients with schizophrenia.166,167 Moreover, the role of this region in regulating subcortical DA activity168,169 makes PFC lesions particularly amenable to study in the current behavioural testing paradigms validated in pharmacological models of schizophrenia. Lesions of the adult rat PFC result in an enduring hyper-responsiveness to stress,170,171 as well as transient increases in locomotor exploration and amphetamine-induced stereotypy.172,173,174,175 As well, adult rats with PFC lesions show reduced PPI after apomorphine injections176 and reduced cataleptic response to haloperidol,174 suggesting that postsynaptic striatal DA neurotransmission is increased.
The hippocampal formation has also received a great deal of experimental attention because this region modulates PFC activity, especially at the level of its projections to the NAC.59 Thus, it exerts direct control over the mesolimbic dopaminergic system, believed to be affected in schizophrenia.177 Aspiration lesions of the hippocampus in adult rats have been reported to selectively increase locomotor behaviour after amphetamine or DA receptor agonist administration.178 Interestingly, excitotoxic lesions of the dorsal hippocampus (DH) and ventral hippocampus (VH) produce different behavioural profiles, with DH lesions having no effect on amphetamine-induced locomotion179 and VH lesions resulting in increased spontaneous and DA-agonist-induced locomotor activity.180,181,182 The behavioural changes induced by VH lesions have been detected approximately 2 weeks postoperatively.174,176,181 However, these rats do not show PPI deficits in the absence of apomorphine176 or exaggerated locomotion in response to stress. As well, they exhibit a decrease in stereotypic behaviours.183
A similar model involves the intracerebroventricular (ICV) administration of kainic acid,184,185 which results in immediate as well as delayed neuronal loss in the DH and has been proposed as an animal model of neurodegeneration that may be comparable to schizophrenia.184 Unlike the DH lesion model, however, ICV administration of kainic acid has been reported to enhance locomotor response to novelty and saline injection, as well as to amphetamine and MK-801 administration.186 Increased DA receptor binding in the NAC has also been reported in this model,185 similar to that reported after adult hippocampal lesions.178
The thalamus is another potential target for lesion studies because this region is generally believed to act as a “relay station,” filtering or gating sensory information.187 Abnormalities in limbic corticothalamic circuitry that correspond with deficiencies in sensorimotor gating (i.e., PPI) have been observed in schizophrenia.188 Some, but not all, post-mortem studies have revealed reductions in thalamic volume,189,190 and similar reductions have also been found in nonpsychotic siblings of schizophrenic patients.191 Reduced PPI has been found in rats with thalamic lesions, but this reduction was only apparent after an infusion of muscimol, a GABAA agonist.192
Despite reasonable claims for predictive and face validity for many of these adult lesion models, the size and “adult nature” of the lesions limits their construct validity as animal models of schizophrenia.
Neonatal lesion models
A number of neonatal lesion models have also been developed to test neurodevelopmental theories of schizophrenia.6 One of the principal advantages of these models is the ability to demonstrate a delayed onset of symptoms that corresponds to the clinical presentation of schizophrenia in humans. For example, Goldman193 first showed that perinatal ablations of the PFC did not impair performance on a delayed response task until after adolescence. One possible explanation for this postpubertal emergence is that other brain regions compensate for damage before puberty, but by adolescence the brain becomes developmentally committed to use the cortex for this activity. This interpretation is consistent with data suggesting that limbic abnormalities evident in schizophrenia are associated with an early developmental injury that does not manifest until adulthood.149,166,194 Previously, in rats that received PFC lesions as neonates, we reported a postpubertal increase in locomotor activity in response to amphetamine and stress, with concomitant changes in DA receptors and DA release in the NAC.195,196 Although discrepant data have been reported,197 the behavioural and biochemical profile of these animals remains to be fully characterized.
In contrast, most of the research on neonatal lesion models of schizophrenia have focused on the VH. This is not surprising given the major role of this region in regulating subcortical DA.59 Rats with neonatal excitotoxic lesions of the VH demonstrate delayed onset of hyperdopaminergic behaviours. Although these animals are behaviourally similar to controls at postnatal day 35 (PD35), postpubertally at PD56 they display increased locomotion in response to novelty, forced swim stress and after saline or amphetamine injection.183,198 Interestingly, these behavioural effects are not observed after neonatal DH lesions. The postpubertal changes induced by neonatal VH lesions are believed to be the result of increased mesolimbic DA function but reduced DA release.199,200 The PD56 rats also exhibit reduced haloperidol-induced catalepsy and enhanced apomorphine-induced stereotypies.201 As in the case of dopaminergic pharmacological models, rats with VH neonatal lesions also show impaired PPI.202,203,204 Further, the behavioural deficits exhibited by these animals are ameliorated after antipsychotic administration.174 Neonatal VH lesions also cause disturbed latent inhibition comparable to that seen in patients with schizophrenia.205
In terms of negative symptoms of schizophrenia, alterations in social interaction and increased aggressive behaviour have also been reported in rats with neonatal VH lesions.206,207 However, deficits in social interaction are present both pre- and postpubertally.206 Further, the atypical antipsychotic clozapine had no effect on social interaction deficits despite ameliorating hyperlocomotion in this model. The source of these social interaction deficits is unclear but does not appear to involve anxiety; there were no differences observed between rats with lesions and control rats in the elevated plus maze.207 Interestingly, lesions of the VH in adult rats have no effect on social behaviour, suggesting that lesion-induced impairments are of a neurodevelopmental nature. These findings are not limited to rodent studies; similar results have also been obtained in primates with perinatal lesions of the medial temporal lobe, where greater deficits in locomotor activity and social interaction were observed with perinatal than with adult lesions.208,209
Interestingly, ICV kainic acid administration in preweanling rats has also been reported to produce a predominantly delayed neuronal loss in the hippocampus, unlike the immediate effects observed with adult lesions.210
One possibility for the postpubertal emergence of symptoms in the VH model may be a delayed effect on the dopaminergic system that occurs later in life. Both hippocampal physiology and the dopaminergic system are influenced by sexual maturation and related hormonal changes.211 It is also possible that the VH lesion affects the development of other neural systems, such as the PFC, which regulates mesolimbic DA activity during stress.170,212,213 Interestingly, PFC physiology is immature prepubertally and continues to develop into adulthood.214 In support of the theory of hypoactive glutamatergic function in the PFC in schizophrenia, increased specific glutamate binding and decreased [3H]aspartate release in the frontal cortex of adult rats after neonatal VH lesions has been reported.215 As well, Bernstein et al216 found reduced numbers of neurons and increased immunostaining for ornithine decarboxylase and nitric oxide synthase in the PFC.
Neonatal lesions of the VH have also been shown to alter levels of DA and its metabolites in the NAC.181,182,200 However, despite the enhanced locomotor response to amphetamine in these rats, DA release is attenuated in both the PFC and NAC in response to amphetamine or stress in these animals.199,200,217,218 In a similar model involving neonatal temporal lobe lesions in primates, PFC regulation of DA release in the NAC is disrupted.219 Neonatal VH lesions have also been reported to be associated with increased sensitivity to D2 receptor agonists such as quinpirole,220 and altered levels of DA receptors have been reported in various brain regions in this model.198,215,221
One caveat with all experimentally induced lesion models is that they reflect far greater damage than what is seen in the brains of those who had schizophrenia. However, the postpubertal emergence of several DA-related behaviours (e.g., increased locomotor activity, reduced PPI) and their amelioration in response to antipsychotics demonstrate the comparatively good face, predictive and construct validity of these models. Although the relevance of hyperlocomotion to schizophrenic symptoms may be contentious, this behaviour can be reliably induced in animals in response to psychostimulants and may thus serve as a useful behavioural correlate of altered dopaminergic function.
Conclusions
One of the most difficult aspects of modelling schizophrenia in animals has been the lack of a clear and explicit conceptual framework for this disorder. Despite the prevalence of the neurodevelopmental theory, it has remained difficult to develop specific hypotheses that can be tested experimentally. Implicit in this task is the importance of developing models that allow for both the confirmation and the falsification of specific hypotheses, a cardinal feature of scientific investigation that is sometimes lacking in modelling exercises. Accordingly, the most appropriate use of many of the current models is in the testing of narrowly focused hypotheses regarding specific aspects of the disorder.
The neonatal VH lesion model holds promise in helping to elucidate the underlying molecular circuitry involved in the pathophysiology of schizophrenia. Clearly, the direct relevance of severe damage models to the subtle and widespread changes observed in the schizophrenic brain is questionable. But models of this sort may help to illuminate what has historically been one of the major difficulties with the neurodevelopmental hypothesis of schizophrenia, namely, explaining how brain abnormalities that occur in early life could result in the delayed manifestation of symptoms in adulthood.
As was first demonstrated by Kennard,222 the degree of functional sparing after brain damage increases as the postinjury interval increases. Based on this principle, it would be expected that any damage occurring in early life would be undetectable by adulthood. Moreover, it is now well established that the immature brain is capable of a high degree of plasticity or sparing of behavioural function after injury.223,224 However, it must be emphasized that this high degree of plasticity occurs during narrow “windows of opportunity” in development.225 For example, rats lesioned on postnatal day 1 (PD1) show much less dendritic branching and more severe water task deficits when tested as adults, whereas those lesioned on PD10 show considerable dendritic sprouting and sparing of function relative to those lesioned as adults.224 These results suggest that neurodevelopmental windows exist when brain damage can or cannot be successfully compensated for, depending on the brain region involved. An even narrower window of opportunity was demonstrated recently by Ikonomidou et al,226 where blockade of NMDA receptors for even a few hours during late fetal development or early neonatal life triggered apoptotic neurodegeneration in the developing rat brain.
What about the development of new models of schizophrenia? Historically, modelling exercises have focused on alterations in specific neurotransmitter systems, but the current pharmacological models appear to have reached the limit of their predictive or explanatory capabilities. One possible further avenue, building on the pharmacological approach, is the examination of synaptic terminal proteins in general. Increasing attention is being focused on the role of these proteins in a variety of processes involving plasticity, particularly in learning and memory.227,228,229 Changes in synaptic proteins such synapsin, synaptophysin and SNAP-25 have been reported in schizophrenia.230,231,232,233,234,235 More recently, the newly identified synapsin III has been associated with a susceptibility locus for schizophrenia.236,237,238 These findings point toward a role for altered synaptic neurotransmission in this disorder. However, it is important to recognize that the current models serve solely as an intermediate step in our development of more sophisticated frameworks for characterizing neurodevelopmental deficits.
The past decade has also brought tremendous advances in our understanding of molecules that guide the development of the nervous system. Cell adhesion molecules (CAMs) such as NCAM and L1 have already received extensive study, and their role in regulating neurite outgrowth and axon fasciculation are well known.239,240,241,242,243 Previously, we demonstrated reduced levels of embryonic polysialylated isoform (PSA-NCAM) residues in the hippocampus of the schizophrenic brain.244 Further, NCAM-180 knockout mice reveal deficits in neuronal migration,245 increased ventricle size and PPI deficits246 reminiscent of schizophrenia.
Several gene families that regulate the development of the cerebral cortex have been discovered that may be relevant in modelling schizophrenia. For example, reelin, an extracellular matrix glycoprotein secreted by Cajal-Retzius cells in the marginal zone during development, is crucial for the radial organization of the cortical plate and eventual cortical lamination.247,248 The reeler mouse, a natural mutant with disrupted reelin, displays aberrant migration of cortical neurons and motor ataxia,249 and decreased levels of reelin have been reported in several brain regions of patients with schizophrenia.250 Reelin has thus been suggested to be a putative vulnerability factor in schizophrenia. Moreover, defective corticogenesis and reduction in reelin expression in cortex and hippocampus have recently been reported in prenatally infected neonatal mice.251
Other neurodevelopmental molecules of interest include the netrin family of axon guidance molecules known to act as chemoattractants during development.252,253,254,255,256 More recently, the Eph family of receptor tyrosine kinases and their transmembrane and GPI-anchored ligands known as ephrins have been implicated in the regulation of axon guidance in various CNS regions.257,258,259,260 In particular, members of this family of molecules seem to inhibit axon outgrowth261,262,263,264,265 and may prove of great interest in the study of schizophrenia. Similarly, the semaphorin family of axon guidance molecules represent a second major inhibitory system for axonal pathfinding,266,267 although they may also have some attractive roles as well.268,269,270,271 This family consists of a large number of transmembrane and soluble semaphorins that bind to complexes of transmembrane receptors known as neuropilins and plexins.272,273
These families of axon guidance molecules work together in an intricate fashion to regulate axon development. However, they form the barest beginning of our understanding of developmental processes at a molecular level. New molecules are constantly being discovered, and as the interplay between these factors becomes better understood, it is possible that more sophisticated animal models of schizophrenia based on perturbations of these molecules may be developed.
Much of the current research into the development of animal models has benefited from tremendous advances in our understanding of the role of genetic factors in human development and disease. In particular, targeted gene deletion and overexpression techniques in animals have helped to elucidate the biochemical pathways underlying many human conditions. Although schizophrenia is a highly heritable disorder, it is generally believed to involve the interaction of a large number of genes,236,274,275 and it is thus unlikely to be faithfully modelled in its entirety by this approach. However, even limited models can have profound implications for our understanding of human disorders. There are already a large number of promising candidate genes available for study in schizophrenia, including many of the neurodevelopmental markers listed above as well as classical neurotransmitter signalling components (for a recent review, see Lipska and Weinberger6).
It is in this manner than the various neurodegenerative–neurodevelopmental and genetic–environmental aspects of the disorder may ultimately be united. Multiple factors at work over time may contribute to abnormal brain maturation up to puberty, with the ensuing emergence of symptoms and their progression over time. A greater understanding of the various genetic factors involved and the environmental forces that modulate their expression over time may help us to develop more sophisticated animal models. Ultimately, these future models may help to expand our knowledge of this poorly understood disorder, which strikes at the very core of what it means to be human.
Acknowledgments
This work was supported by the Canadian Institutes of Health Research (CIHR). E.R.M. holds a post-doctoral fellowship from the CIHR. L.K.S. is a chercheur national of the Fonds de la recherche en santé du Québec.
Footnotes
Competing interests: None declared.
Correspondence to: Dr. Lalit K. Srivastava, Douglas Hospital Research Centre, 6875 LaSalle Blvd., Verdun QC H4H 1R3; srilal@douglas.mcgill.ca
Submitted Oct. 23, 2000 Revised Feb. 28, 2001 Accepted Mar. 19, 2001
References
- 1.Woods BT. Is schizophrenia a progressive neurodevelopmental disorder? Toward a unitary pathogenetic mechanism. Am J Psychiatry 1998;155(12):1661-70. [DOI] [PubMed]
- 2.Miller R. Schizophrenia as a progressive disorder: relations to EEG, CT, neuropathological and other evidence. Prog Neurobiol 1989;33(1):17-44. [DOI] [PubMed]
- 3.Keshavan MS, Anderson S, Pettegrew JW. Is schizophrenia due to excessive synaptic pruning in the prefrontal cortex? The Feinberg hypothesis revisited. J Psychiatr Res 1994;28(3):239-65. [DOI] [PubMed]
- 4.DeLisi LE. Is schizophrenia a lifetime disorder of brain plasticity, growth and aging? Schizophr Res 1997;23(2):119-29. [DOI] [PubMed]
- 5.Crow TJ. Schizophrenia as failure of hemispheric dominance for language. Trends Neurosci 1997;20(8):339-43. [DOI] [PubMed]
- 6.Lipska BK, Weinberger DR. To model a psychiatric disorder in animals. Schizophrenia as a reality test. Neuropsychopharmacology 2000;23(3):223-39. [DOI] [PubMed]
- 7.Geyer MA, Markou A. Animal models of psychiatric disorders. In: Bloom FE, Kupfer DJ, editors. Psychopharmacology: the fourth generation of progress. New York: Raven Press; 1995. p. 787-97.
- 8.Cowan WM, Harter DH, Kandel ER. The emergence of modern neuroscience: some implications for neurology and psychiatry. Annu Rev Neurosci 2000;23:343-91. [DOI] [PubMed]
- 9.Gold JM, Hermann BP, Randolph C, Wyler AR, Goldberg TE, Weinberger DR. Schizophrenia and temporal lobe epilepsy. A neuropsychological analysis. Arch Gen Psychiatry 1994;51(4): 265-72. [DOI] [PubMed]
- 10.Mirsky AF. Research on schizophrenia in the NIMH Laboratory of Psychology and Psychopathology, 1954–1987. Schizophr Bull 1988;14(2):151-6. [DOI] [PubMed]
- 11.Andreasen NC. Symptoms, signs, and diagnosis of schizophrenia. Lancet 1995;346:477-81. [DOI] [PubMed]
- 12.Cutting J. Descriptive psychopathology. In: Hirsch SR, Weinberger DR, editors. Schizophrenia. Oxford: Blackwell Science; 1995. p. 15-27.
- 13.Davidson L, McGlashan TH. The varied outcomes of schizophrenia. Can J Psychiatry 1997;42(1):34-43. [DOI] [PubMed]
- 14.Huber G. The heterogeneous course of schizophrenia. Schizophr Res 1997;28(2-3):177-85. [DOI] [PubMed]
- 15.Thara R, Eaton WW. Outcome of schizophrenia: the Madras longitudinal study. Aust N Z J Psychiatry 1996;30(4):516-22. [DOI] [PubMed]
- 16.Thara R, Rajkumar S. Gender differences in schizophrenia. Results of a follow-up study from India. Schizophr Res 1992;7(1): 65-70. [DOI] [PubMed]
- 17.Kendler KS, Diehl SR. The genetics of schizophrenia: a current, genetic-epidemiologic perspective. Schizophr Bull 1993;19(2): 261-85. [DOI] [PubMed]
- 18.Tsuang MT, Gilbertson MW, Faraone SV. The genetics of schizophrenia. Current knowledge and future directions. Schizophr Res 1991;4(2):157-71. [DOI] [PubMed]
- 19.Moldin SO, Gottesman II. At issue: genes, experience, and chance in schizophrenia — positioning for the 21st century. Schizophr Bull 1997;23(4):547-61. [DOI] [PubMed]
- 20.Swerdlow NR, Geyer MA. Using an animal model of deficient sensorimotor gating to study the pathophysiology and new treatments of schizophrenia. Schizophr Bull 1998;24(2):285-301. [DOI] [PubMed]
- 21.Moser PC, Hitchcock JM, Lister S, Moran PM. The pharmacology of latent inhibition as an animal model of schizophrenia. Brain Res Brain Res Rev 2000;33(2-3):275-307. [DOI] [PubMed]
- 22.Costall B, Naylor RJ. Animal neuropharmacology and its prediction of clinical response. In: Hirsch SR, Weinberger DR, editors. Schizophrenia. Oxford: Blackwell Science; 1995. p. 401-24.
- 23.Kokkinidis L, Anisman H. Amphetamine models of paranoid schizophrenia: an overview and elaboration of animal experimentation. Psychol Bull 1980;88(3):551-79. [PubMed]
- 24.Robinson TE, Becker JB. Enduring changes in brain and behavior produced by chronic amphetamine administration: a review and evaluation of animal models of amphetamine psychosis. Brain Res 1986;396(2):157-98. [DOI] [PubMed]
- 25.Seeman P. Dopamine receptors and the dopamine hypothesis of schizophrenia. Synapse 1987;1(2):133-52. [DOI] [PubMed]
- 26.Carlsson A. The dopamine theory revisited. In: Hirsch SR, Weinberger DR, editors. Schizophrenia. Oxford: Blackwell Science; 1995. p. 379-400.
- 27.Dworkin RH, Opler LA. Simple schizophrenia, negative symptoms, and prefrontal hypodopaminergia. Am J Psychiatry 1992;149(9):1284-5. [DOI] [PubMed]
- 28.Abi-Dargham A, Gil R, Krystal J, Baldwin RM, Seibyl JP, Bowers M, et al. Increased striatal dopamine transmission in schizophrenia: confirmation in a second cohort. Am J Psychiatry 1998;155(6):761-7. [DOI] [PubMed]
- 29.Breier A, Su TP, Saunders R, Carson RE, Kolachana BS, de Bartolomeis A, et al. Schizophrenia is associated with elevated amphetamine-induced synaptic dopamine concentrations: evidence from a novel positron emission tomography method. Proc Natl Acad Sci U S A 1997;94(6):2569-74. [DOI] [PMC free article] [PubMed]
- 30.Laruelle M. Imaging dopamine transmission in schizophrenia. A review and meta-analysis. Q J Nucl Med 1998;42(3):211-21. [PubMed]
- 31.Angrist BM, Gershon S. The phenomenology of experimentally induced amphetamine psychosis — preliminary observations. Biol Psychiatry 1970;2(2):95-107. [PubMed]
- 32.Morland J. Toxicity of drug abuse — amphetamine designer drugs (ecstasy): mental effects and consequences of single dose use. Toxicol Lett 2000;112-113:147-52. [DOI] [PubMed]
- 33.Lieberman JA, Alvir J, Geisler S, Ramos-Lorenzi J, Woerner M, Novacenko H, et al. Methylphenidate response, psychopathology and tardive dyskinesia as predictors of relapse in schizophrenia. Neuropsychopharmacology 1994;11(2):107-18. [DOI] [PubMed]
- 34.Lieberman JA, Kane JM, Alvir J. Provocative tests with psychostimulant drugs in schizophrenia. Psychopharmacology (Berl) 1987;91(4):415-33. [DOI] [PubMed]
- 35.Levy DL, Smith M, Robinson D, Jody D, Lerner G, Alvir J, et al. Methylphenidate increases thought disorder in recent onset schizophrenics, but not in normal controls. Biol Psychiatry 1993;34(8):507-14. [DOI] [PubMed]
- 36.Kebabian JW, Calne DB. Multiple receptors for dopamine. Nature 1979;277:93-6. [DOI] [PubMed]
- 37.Baldessarini RJ, Tarazi FI. Brain dopamine receptors: a primer on their current status, basic and clinical. Harv Rev Psychiatry 1996;3(6):301-25. [DOI] [PubMed]
- 38.Hartman DS, Civelli O. Dopamine receptor diversity: molecular and pharmacological perspectives. Prog Drug Res 1997;48:173-94. [DOI] [PubMed]
- 39.Lachowicz JE, Sibley DR. Molecular characteristics of mammalian dopamine receptors. Pharmacol Toxicol 1997;81(3):105-13. [DOI] [PubMed]
- 40.Seeman P, Lee T, Chau-Wong M, Wong K. Antipsychotic drug doses and neuroleptic/dopamine receptors. Nature 1976;261:717-9. [DOI] [PubMed]
- 41.Creese I, Burt DR, Snyder SH. Dopamine receptor binding predicts clinical and pharmacological potencies of antischizophrenic drugs. Science 1976;192:481-3. [DOI] [PubMed]
- 42.Seeman P, Kapur S. Schizophrenia: more dopamine, more D2 receptors. Proc Natl Acad Sci U S A 2000;97(14):7673-5. [DOI] [PMC free article] [PubMed]
- 43.Zakzanis KK, Hansen KT. Dopamine D2 densities and the schizophrenic brain. Schizophr Res 1998;32(3):201-6. [DOI] [PubMed]
- 44.Wong DF, Wagner HN Jr, Tune LE, Dannals RF, Pearlson GD, Links JM, et al. Positron emission tomography reveals elevated D2 dopamine receptors in drug-naive schizophrenics. Science 1986;234:1558-63. [DOI] [PubMed]
- 45.Abi-Dargham A, Rodenhiser J, Printz D, Zea-Ponce Y, Gil R, Kegeles LS, et al. Increased baseline occupancy of D2 receptors by dopamine in schizophrenia. Proc Natl Acad Sci U S A 2000; 97(14):8104-9. [DOI] [PMC free article] [PubMed]
- 46.Gurevich EV, Bordelon Y, Shapiro RM, Arnold SE, Gur RE, Joyce JN. Mesolimbic dopamine D3 receptors and use of antipsychotics in patients with schizophrenia. A postmortem study. Arch Gen Psychiatry 1997;54(3):225-32. [DOI] [PubMed]
- 47.Den Boer JA, van Megen HJ, Fleischhacker WW, Louwerens JW, Slaap BR, Westenberg HG, et al. Differential effects of the D1 DA receptor antagonist SCH39166 on positive and negative symptoms of schizophrenia. Psychopharmacology (Berl) 1995; 121(3):317-22. [DOI] [PubMed]
- 48.Seeman P, Corbett R, Van Tol HH. Atypical neuroleptics have low affinity for dopamine D2 receptors or are selective for D4 receptors. Neuropsychopharmacology 1997;16(2):93-110. [DOI] [PubMed]
- 49.Reynolds GP. Dopamine D4 receptors in schizophrenia? J Neurochem 1996;66(2):881-3. [PubMed]
- 50.Harrison PJ. The neuropathology of schizophrenia. A critical review of the data and their interpretation. Brain 1999;122:593-624. [DOI] [PubMed]
- 51.Sharp T, Zetterstrom T, Ljungberg T, Ungerstedt U. A direct comparison of amphetamine-induced behaviours and regional brain dopamine release in the rat using intracerebral dialysis. Brain Res 1987;401(2):322-30. [DOI] [PubMed]
- 52.Pijnenburg AJ, Honig WM, Van Rossum JM. Inhibition of d-amphetamine-induced locomotor activity by injection of haloperidol into the nucleus accumbens of the rat. Psychopharmacologia 1975;41(2):87-95. [DOI] [PubMed]
- 53.Swerdlow NR, Braff DL, Taaid N, Geyer MA. Assessing the validity of an animal model of deficient sensorimotor gating in schizophrenic patients. Arch Gen Psychiatry 1994;51(2):139-54. [DOI] [PubMed]
- 54.Braff D, Stone C, Callaway E, Geyer M, Glick I, Bali L. Prestimulus effects on human startle reflex in normals and schizophrenics. Psychophysiology 1978;15(4):339-43. [DOI] [PubMed]
- 55.Braff DL, Geyer MA. Sensorimotor gating and schizophrenia. Human and animal model studies. Arch Gen Psychiatry 1990; 47(2):181-8. [DOI] [PubMed]
- 56.Braff DL, Grillon C, Geyer MA. Gating and habituation of the startle reflex in schizophrenic patients. Arch Gen Psychiatry 1992;49(3):206-15. [DOI] [PubMed]
- 57.Davis KL, Kahn RS, Ko G, Davidson M. Dopamine in schizophrenia: a review and reconceptualization. Am J Psychiatry 1991;148(11):1474-86. [DOI] [PubMed]
- 58.Joyce JN, Meador-Woodruff JH. Linking the family of D2 receptors to neuronal circuits in human brain: insights into schizophrenia. Neuropsychopharmacology 1997;16(6):375-84. [DOI] [PubMed]
- 59.Grace AA. Gating of information flow within the limbic system and the pathophysiology of schizophrenia. Brain Res Brain Res Rev 2000;31(2-3):330-41. [DOI] [PubMed]
- 60.Crow TJ. Two syndromes of schizophrenia as one pole of the continuum of psychosis: a concept of the nature of the pathogen and its genomic locus. In: Henn FA, DeLisi LE, editors. Handbook of schizophrenia: the neurochemistry and neuropharmacology of schizophrenia. Amsterdam: Elsevier; 1987. p. 17-48.
- 61.Domino EF, Luby ED. Abnormal mental states induced by phencyclidine as a model of schizophrenia. In: Domino EF, editor. PCP(phencyclidine): historical and current perspectives. Ann Arbor: NPP Books; 1981. p. 401-18.
- 62.Angrist BM. Neurochemistry and neuropharmacology of schizophrenia. In: Henn FA, DeLisi LE, editors. Pharmacological models of schizophrenia. Amsterdam: Elsevier; 1987. p. 391-424.
- 63.Lodge D, Aran JA, Church J, Davies SN, Martin DA, Zeman S. Excitatory amino acids and phencyclidine drugs. In: Hicks TP, Lodge D, McLennan H, editors. Excitatory amino acid transmission. New York: Alan Liss; 1987. p. 83-90.
- 64.Javitt DC, Zukin SR. Recent advances in the phencyclidine model of schizophrenia. Am J Psychiatry 1991;148(10):1301-8. [DOI] [PubMed]
- 65.Krystal JH, Karper LP, Seibyl JP, Freeman GK, Delaney R, Bremner JD, et al. Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry 1994;51(3):199-214. [DOI] [PubMed]
- 66.Lahti AC, Holcomb HH, Medoff DR, Tamminga CA. Ketamine activates psychosis and alters limbic blood flow in schizophrenia. Neuroreport 1995;6(6):869-72. [DOI] [PubMed]
- 67.Lahti AC, Koffel B, LaPorte D, Tamminga CA. Subanesthetic doses of ketamine stimulate psychosis in schizophrenia. Neuropsychopharmacology 1995;13(1):9-19. [DOI] [PubMed]
- 68.Malhotra AK, Pinals DA, Weingartner H, Sirocco K, Missar CD, Pickar D, et al. NMDA receptor function and human cognition: the effects of ketamine in healthy volunteers. Neuropsychopharmacology 1996;14(5):301-7. [DOI] [PubMed]
- 69.Malhotra AK, Pinals DA, Adler CM, Elman I, Clifton A, Pickar D, et al. Ketamine-induced exacerbation of psychotic symptoms and cognitive impairment in neuroleptic-free schizophrenics. Neuropsychopharmacology 1997;17(3):141-50. [DOI] [PubMed]
- 70.Breier A, Adler CM, Weisenfeld N, Su TP, Elman I, Picken L, et al. Effects of NMDA antagonism on striatal dopamine release in healthy subjects: application of a novel PET approach. Synapse 1998;29(2):142-7. [DOI] [PubMed]
- 71.Coyle JT. The glutamatergic dysfunction hypothesis for schizophrenia. Harv Rev Psychiatry 1996;3(5):241-53. [DOI] [PubMed]
- 72.Deutsch SI, Mastropaolo J, Schwartz BL, Rosse RB, Morihisa JM. A “glutamatergic hypothesis” of schizophrenia. Rationale for pharmacotherapy with glycine. Clin Neuropharmacol 1989; 12(1):1-13. [PubMed]
- 73.Olney JW, Farber NB. Glutamate receptor dysfunction and schizophrenia. Arch Gen Psychiatry 1995;52(12):998-1007. [DOI] [PubMed]
- 74.Maren S. Long-term potentiation in the amygdala: a mechanism for emotional learning and memory. Trends Neurosci 1999;22(12):561-7. [DOI] [PubMed]
- 75.Grunwald T, Beck H, Lehnertz K, Blumcke I, Pezer N, Kurthen M, et al. Evidence relating human verbal memory to hippocampal N-methyl-D-aspartate receptors. Proc Natl Acad Sci U S A 1999;96(21):12085-9. [DOI] [PMC free article] [PubMed]
- 76.Kornhuber J, Mack-Burkhardt F, Riederer P, Hebenstreit GF, Reynolds GP, Andrews HB, et al. [3H]MK-801 binding sites in postmortem brain regions of schizophrenic patients. J Neural Transm 1989;77(2-3):231-6. [DOI] [PubMed]
- 77.Sherman AD, Davidson AT, Baruah S, Hegwood TS, Waziri R. Evidence of glutamatergic deficiency in schizophrenia. Neurosci Lett 1991;121(1-2):77-80. [DOI] [PubMed]
- 78.Macciardi F, Lucca A, Catalano M, Marino C, Zanardi R, Smeraldi E. Amino acid patterns in schizophrenia: some new findings. Psychiatry Res 1990;32(1):63-70. [DOI] [PubMed]
- 79.Kerwin R, Patel S, Meldrum B. Quantitative autoradiographic analysis of glutamate binding sites in the hippocampal formation in normal and schizophrenic brain post mortem. Neuroscience 1990;39(1):25-32. [DOI] [PubMed]
- 80.Eastwood SL, McDonald B, Burnet PW, Beckwith JP, Kerwin RW, Harrison PJ. Decreased expression of mRNAs encoding non-NMDA glutamate receptors GluR1 and GluR2 in medial temporal lobe neurons in schizophrenia. Brain Res Mol Brain Res 1995;29(2):211-23. [DOI] [PubMed]
- 81.Porter RH, Eastwood SL, Harrison PJ. Distribution of kainate receptor subunit mRNAs in human hippocampus, neocortex and cerebellum, and bilateral reduction of hippocampal GluR6 and KA2 transcripts in schizophrenia. Brain Res 1997;751(2):217-31. [DOI] [PubMed]
- 82.Carlsson M, Carlsson A. Schizophrenia: a subcortical neurotransmitter imbalance syndrome? Schizophr Bull 1990;16(3):425-32. [DOI] [PubMed]
- 83.Deakin JF, Simpson MD. A two-process theory of schizophrenia: evidence from studies in post-mortem brain. J Psychiatr Res 1997;31(2):277-95. [DOI] [PubMed]
- 84.Jentsch JD, Redmond DE Jr, Elsworth JD, Taylor JR, Youngren KD, Roth RH. Enduring cognitive deficits and cortical dopamine dysfunction in monkeys after long-term administration of phencyclidine. Science 1997;277:953-5. [DOI] [PubMed]
- 85.Geyer MA, Segal DS, Greenberg BD. Increased startle responding in rats treated with phencyclidine. Neurobehav Toxicol Teratol 1984;6(2):161-4. [PubMed]
- 86.Yamada S, Harano M, Annoh N, Nakamura K, Tanaka M. Involvement of serotonin 2A receptors in phencyclidine-induced disruption of prepulse inhibition of the acoustic startle in rats. Biological Psychiatry 1999;46(6):832-8. [DOI] [PubMed]
- 87.Snell LD, Johnson KM. Characterization of the inhibition of excitatory amino acid-induced neurotransmitter release in the rat striatum by phencyclidine-like drugs. J Pharmacol Exp Ther 1986;238(3):938-46. [PubMed]
- 88.Steinpreis RE, Sokolowski JD, Papanikolaou A, Salamone JD. The effects of haloperidol and clozapine on PCP- and amphetamine-induced suppression of social behavior in the rat. Pharmacol Biochem Behav 1994;47(3):579-85. [DOI] [PubMed]
- 89.Sams-Dodd F. Automation of the social interaction test by a video-tracking system: behavioural effects of repeated phencyclidine treatment. J Neurosci Methods 1995;59(2):157-67. [DOI] [PubMed]
- 90.French ED, Vantini G. Phencyclidine-induced locomotor activity in the rat is blocked by 6-hydroxydopamine lesion of the nucleus accumbens: comparisons to other psychomotor stimulants. Psychopharmacology (Berl) 1984;82(1-2):83-8. [DOI] [PubMed]
- 91.Rao TS, Kim HS, Lehmann J, Martin LL, Wood PL. Differential effects of phencyclidine (PCP) and ketamine on mesocortical and mesostriatal dopamine release in vivo. Life Sci 1989;45(12): 1065-72. [DOI] [PubMed]
- 92.Matsuzaki M, Dowling KC. Phencyclidine (PCP): effects of acute and chronic administration on EEG activities in the rhesus monkey. Electroencephalogr Clin Neurophysiol 1985;60(4):356-66. [DOI] [PubMed]
- 93.Hori T, Subramaniam S, Srivastava LK, Quirion R. Behavioral and neurochemical alterations following repeated phencyclidine administration in rats with neonatal ventral hippocampal lesions. Neuropharmacology 2000;39(12):2478-91. [DOI] [PubMed]
- 94.Linn GS, O'Keeffe RT, Schroeder CE, Lifshitz K, Javitt DC. Behavioral effects of chronic phencyclidine in monkeys. Neuroreport 1999;10(13):2789-93. [DOI] [PubMed]
- 95.Chait LD, Balster RL. The effects of acute and chronic phencyclidine on schedule-controlled behavior in the squirrel monkey. J Pharmacol Exp Ther 1978;204(1):77-87. [PubMed]
- 96.Noda Y, Yamada K, Furukawa H, Nabeshima T. Enhancement of immobility in a forced swimming test by subacute or repeated treatment with phencyclidine: a new model of schizophrenia. Br J Pharmacol 1995;116(5):2531-7. [DOI] [PMC free article] [PubMed]
- 97.Jentsch JD, Roth RH. The neuropsychopharmacology of phencyclidine: from NMDA receptor hypofunction to the dopamine hypothesis of schizophrenia. Neuropsychopharmacology 1999;20(3):201-25. [DOI] [PubMed]
- 98.Harrison PJ, Burnet PW. The 5-HT2A (serotonin2A) receptor gene in the aetiology, pathophysiology and pharmacotherapy of schizophrenia. J Psychopharmacol 1997;11(1):18-20. [DOI] [PubMed]
- 99.Kulig K. LSD. Emerg Med Clin North Am 1990;8(3):551-8. [PubMed]
- 100.Penington NJ, Fox AP. Effects of LSD on Ca++ currents in central 5-HT-containing neurons: 5-HT1A receptors may play a role in hallucinogenesis. J Pharmacol Exp Ther 1994;269(3):1160-5. [PubMed]
- 101.Aghajanian GK, Marek GJ. Serotonin model of schizophrenia: emerging role of glutamate mechanisms. Brain Res Brain Res Rev 2000;31(2-3):302-12. [DOI] [PubMed]
- 102.Williams J, McGuffin P, Nothen M, Owen MJ. Meta-analysis of association between the 5-HT2A receptor T102C polymorphism and schizophrenia. EMASS Collaborative Group. European Multicentre Association Study of Schizophrenia [letter]. Lancet 1997;349:1221. [DOI] [PubMed]
- 103.Burnet PW, Eastwood SL, Harrison PJ. [3H]WAY-100635 for 5-HT1A receptor autoradiography in human brain: a comparison with [3H]8-OH-DPAT and demonstration of increased binding in the frontal cortex in schizophrenia. Neurochem Int 1997; 30(6):565-74. [DOI] [PubMed]
- 104.Burnet PW, Eastwood SL, Harrison PJ. 5-HT1A and 5-HT2A receptor mRNAs and binding site densities are differentially altered in schizophrenia. Neuropsychopharmacology 1996;15(5):442-55. [DOI] [PubMed]
- 105.Abi-Dargham A, Laruelle M, Aghajanian GK, Charney D, Krystal J. The role of serotonin in the pathophysiology and treatment of schizophrenia. J Neuropsychiatry Clin Neurosci 1997;9(1):1-17. [DOI] [PubMed]
- 106.Trichard C, Paillere-Martinot ML, Attar-Levy D, Blin J, Feline A, Martinot JL. No serotonin 5-HT2A receptor density abnormality in the cortex of schizophrenic patients studied with PET. Schizophr Res 1998;31(1):13-7. [DOI] [PubMed]
- 107.Meltzer HY. Pre-clinical pharmacology of atypical antipsychotic drugs: a selective review. Br J Psychiatry Suppl 1996;29:23-31. [PubMed]
- 108.Arranz MJ, Munro J, Sham P, Kirov G, Murray RM, Collier DA, et al. Meta-analysis of studies on genetic variation in 5-HT2A receptors and clozapine response. Schizophr Res 1998;32(2):93-9. [DOI] [PubMed]
- 109.Geyer MA, Braff DL. Startle habituation and sensorimotor gating in schizophrenia and related animal models. Schizophr Bull 1987;13(4):643-68. [DOI] [PubMed]
- 110.Geyer MA. Behavioral studies of hallucinogenic drugs in animals: implications for schizophrenia research. Pharmacopsychiatry 1998;31(Suppl 2):73-9. [DOI] [PubMed]
- 111.Gleason SD, Shannon HE. Blockade of phencyclidine-induced hyperlocomotion by olanzapine, clozapine and serotonin receptor subtype selective antagonists in mice. Psychopharmacology (Berl) 1997;129(1):79-84. [DOI] [PubMed]
- 112.Costall B, Domeney AM, Naylor RJ, Tyers MB. Effects of the 5-HT3 receptor antagonist, GR38032F, on raised dopaminergic activity in the mesolimbic system of the rat and marmoset brain. Br J Pharmacol 1987;92(4):881-94. [DOI] [PMC free article] [PubMed]
- 113.Abi-Dargham A, Laruelle M, Lipska B, Jaskiw GE, Wong DT, Robertson DW, et al. Serotonin 5-HT3 receptors in schizophrenia: a postmortem study of the amygdala. Brain Res 1993;616 (1-2):53-7. [DOI] [PubMed]
- 114.Poyurovsky M, Weizman A. Lack of efficacy of the 5-HT3 receptor antagonist granisetron in the treatment of acute neuroleptic-induced akathisia. Int Clin Psychopharmacol 1999;14(6):357-60. [DOI] [PubMed]
- 115.Sirota P, Mosheva T, Shabtay H, Giladi N, Korczyn AD. Use of the selective serotonin 3 receptor antagonist ondansetron in the treatment of neuroleptic-induced tardive dyskinesia. Am J Psychiatry 2000;157(2):287-9. [DOI] [PubMed]
- 116.Briskin JK, Curtis JL. Augmentation of clozapine therapy with ondansetron. Am J Psychiatry 1997;154(8):1171. [DOI] [PubMed]
- 117.Braff DL, Geyer MA. Acute and chronic LSD effects on rat startle: data supporting an LSD — rat model of schizophrenia. Biol Psychiatry 1980;15(6):909-16. [PubMed]
- 118.Japha K, Koch M. Picrotoxin in the medial prefrontal cortex impairs sensorimotor gating in rats: reversal by haloperidol. Psychopharmacology (Berl) 1999;144(4):347-54. [DOI] [PubMed]
- 119.Goldman-Rakic PS, Selemon LD. Functional and anatomical aspects of prefrontal pathology in schizophrenia. Schizophr Bull 1997;23(3):437-58. [DOI] [PubMed]
- 120.Lewis DA, Pierri JN, Volk DW, Melchitzky DS, Woo TU. Altered GABA neurotransmission and prefrontal cortical dysfunction in schizophrenia. Biol Psychiatry 1999;46(5):616-26. [DOI] [PubMed]
- 121.Lewis DA. GABAergic local circuit neurons and prefrontal cortical dysfunction in schizophrenia. Brain Res Brain Res Rev 2000;31(2-3):270-6. [DOI] [PubMed]
- 122.Weinberger DR. From neuropathology to neurodevelopment. Lancet 1995;346:552-7. [DOI] [PubMed]
- 123.Simpson MD, Slater P, Deakin JF, Royston MC, Skan WJ. Reduced GABA uptake sites in the temporal lobe in schizophrenia. Neurosci Lett 1989;107(1-3):211-5. [DOI] [PubMed]
- 124.Benes FM, Vincent SL, Alsterberg G, Bird ED, SanGiovanni JP. Increased GABAA receptor binding in superficial layers of cingulate cortex in schizophrenics. J Neurosci 1992;12(3):924-9. [DOI] [PMC free article] [PubMed]
- 125.Volk DW, Austin MC, Pierri JN, Sampson AR, Lewis DA. Decreased glutamic acid decarboxylase67 messenger RNA expression in a subset of prefrontal cortical gamma-aminobutyric acid neurons in subjects with schizophrenia. Arch Gen Psychiatry 2000;57(3):237-45. [DOI] [PubMed]
- 126.Akbarian S, Kim JJ, Potkin SG, Hagman JO, Tafazzoli A, Bunney WE Jr, et al. Gene expression for glutamic acid decarboxylase is reduced without loss of neurons in prefrontal cortex of schizophrenics. Arch Gen Psychiatry 1995;52(4):258-66. [DOI] [PubMed]
- 127.Carpenter WT Jr, Buchanan RW, Breier A, Kirkpatrick B, Thaker G, Tamminga C. Psychopathology and the question of neurodevelopmental or neurodegenerative disorder. Schizophr Res 1991;5(3):192-4. [DOI] [PubMed]
- 128.Carpenter WT Jr, Buchanan RW, Kirkpatrick B, Tamminga C, Wood F. Strong inference, theory testing, and the neuroanatomy of schizophrenia. Arch Gen Psychiatry 1993;50(10):825-31. [DOI] [PubMed]
- 129.Waddington JL, Lane A, Scully PJ, Larkin C, O'Callaghan E. Neurodevelopmental and neuroprogressive processes in schizophrenia. Antithetical or complementary, over a lifetime trajectory of disease? Psychiatr Clin North Am 1998;21(1):123-49. [DOI] [PubMed]
- 130.DeLisi LE. Regional brain volume change over the life-time course of schizophrenia. J Psychiatr Res 1999;33(6):535-41. [DOI] [PubMed]
- 131.Lieberman JA, Kinon BJ, Loebel AD. Dopaminergic mechanisms in idiopathic and drug-induced psychoses. Schizophr Bull 1990;16(1):97-110. [DOI] [PubMed]
- 132.Loebel AD, Lieberman JA, Alvir JM, Mayerhoff DI, Geisler SH, Szymanski SR. Duration of psychosis and outcome in first-episode schizophrenia. Am J Psychiatry 1992;149(9):1183-8. [DOI] [PubMed]
- 133.Olney JW. Excitatory amino acids and neuropsychiatric disorders. Biol Psychiatry 1989;26(5):505-25. [DOI] [PubMed]
- 134.Wyatt RJ. Neuroleptics and the natural course of schizophrenia. Schizophr Bull 1991;17(2):325-51. [DOI] [PubMed]
- 135.Wyatt RJ. Early intervention for schizophrenia: can the course of the illness be altered? Biol Psychiatry 1995;38(1):1-3. [DOI] [PubMed]
- 136.McGlashan TH, Fenton WS. Subtype progression and pathophysiologic deterioration in early schizophrenia. Schizophr Bull 1993;19(1):71-84. [DOI] [PubMed]
- 137.Weinberger DR, Torrey EF, Neophytides AN, Wyatt RJ. Lateral cerebral ventricular enlargement in chronic schizophrenia. Arch Gen Psychiatry 1979;36(7):735-9. [DOI] [PubMed]
- 138.Harding BN. Malformations of the nervous system. In: Adams JH, Duchen LW, editors. Greenfield's neuropathology, 5th ed. London: Edward Arnold; 1992. p. 521-638.
- 139.Murray RM, Lewis SW. Is schizophrenia a neurodevelopmental disorder? Br Med J (Clin Res Ed) 1987;295:681-2. [DOI] [PMC free article] [PubMed]
- 140.Weinberger DR. Implications of normal brain development for the pathogenesis of schizophrenia. Arch Gen Psychiatry 1987; 44(7):660-9. [DOI] [PubMed]
- 141.Roberts GW. Schizophrenia: a neuropathological perspective. Br J Psychiatry 1991;158:8-17. [DOI] [PubMed]
- 142.Bloom FE. Advancing a neurodevelopmental origin for schizophrenia. Arch Gen Psychiatry 1993;50(3):224-7. [DOI] [PubMed]
- 143.Roberts GW, Royston MC, Weinberger DR. Schizophrenia. In: Graham DI, Lantos PL, editors. Greenfield's neuropathology, 6th ed. London: Edward Arnold; 1997. p. 897-929.
- 144.Feinberg I. Schizophrenia: caused by a fault in programmed synaptic elimination during adolescence? J Psychiatr Res 1982; 17(4):319-34. [DOI] [PubMed]
- 145.Murray RM. Neurodevelopmental schizophrenia: the rediscovery of dementia praecox. Br J Psychiatry Suppl 1994;25:6-12. [PubMed]
- 146.Murray RM, O'Callaghan E, Castle DJ, Lewis SW. A neurodevelopmental approach to the classification of schizophrenia. Schizophr Bull 1992;18(2):319-32. [DOI] [PubMed]
- 147.Green MF, Satz P, Gaier DJ, Ganzell S, Kharabi F. Minor physical anomalies in schizophrenia. Schizophr Bull 1989;15(1):91-9. [DOI] [PubMed]
- 148.Erlenmeyer-Kimling L, Cornblatt B. High-risk research in schizophrenia: a summary of what has been learned. J Psychiatr Res 1987;21(4):401-11. [DOI] [PubMed]
- 149.Fish B, Marcus J, Hans SL, Auerbach JG, Perdue S. Infants at risk for schizophrenia: sequelae of a genetic neurointegrative defect. A review and replication analysis of pandysmaturation in the Jerusalem Infant Development Study. Arch Gen Psychiatry 1992;49(3):221-35. [DOI] [PubMed]
- 150.Waltrip RW, Buchanan RW, Summerfelt A, Breier A, Carpenter WT Jr, Bryant NL, et al. Borna disease virus and schizophrenia. Psychiatry Res 1995;56(1):33-44. [DOI] [PubMed]
- 151.Yamaguchi K, Sawada T, Naraki T, Igata-Yi R, Shiraki H, Horii Y, et al. Detection of borna disease virus-reactive antibodies from patients with psychiatric disorders and from horses by electrochemiluminescence immunoassay. Clin Diagn Lab Immunol 1999;6(5):696-700. [DOI] [PMC free article] [PubMed]
- 152.Torrey EF. A viral-anatomical explanation of schizophrenia. Schizophr Bull 1991;17(1):15-8. [DOI] [PubMed]
- 153.Yolken RH, Torrey EF. Viruses, schizophrenia, and bipolar disorder. Clin Microbiol Rev 1995;8(1):131-45. [DOI] [PMC free article] [PubMed]
- 154.Brake WG, Boksa P, Gratton A. Effects of perinatal anoxia on the acute locomotor response to repeated amphetamine administration in adult rats. Psychopharmacology (Berl) 1997;133(4):389-95. [DOI] [PubMed]
- 155.Dalman C, Allebeck P, Cullberg J, Grunewald C, Koster M. Obstetric complications and the risk of schizophrenia: a longitudinal study of a national birth cohort. Arch Gen Psychiatry 1999;56(3):234-40. [DOI] [PubMed]
- 156.Cannon TD, Mednick SA. Fetal neural development and adult schizophrenia: an elaboration of the paradigm. In: Mednick SA, Cannon TD, Barr CE, Lyon M, editors. Fetal neural development and adult schizophrenia. Cambridge: Cambridge University Press; 1991. p. 227-37.
- 157.Zornberg GL, Buka SL, Tsuang MT. The problem of obstetrical complications and schizophrenia. Schizophr Bull 2000;26(2): 249-56. [DOI] [PubMed]
- 158.Brake WG, Noel MB, Boksa P, Gratton A. Influence of perinatal factors on the nucleus accumbens dopamine response to repeated stress during adulthood: an electrochemical study in the rat. Neuroscience 1997;77(4):1067-76. [DOI] [PubMed]
- 159.El Khodor BF, Boksa P. Long-term reciprocal changes in dopamine levels in prefrontal cortex versus nucleus accumbens in rats born by Caesarean section compared to vaginal birth. Exp Neurol 1997;145(1):118-29. [DOI] [PubMed]
- 160.El Khodor BF, Boksa P. Birth insult increases amphetamine-induced behavioral responses in the adult rat. Neuroscience 1998;87(4):893-904. [DOI] [PubMed]
- 161.Boksa P, Wilson D, Rochford J. Responses to stress and novelty in adult rats born vaginally, by cesarean section or by cesarean section with acute anoxia. Biol Neonate 1998;74(1):48-59. [DOI] [PubMed]
- 162.El Khodor BF, Boksa P. Transient birth hypoxia increases behavioral responses to repeated stress in the adult rat. Behav Brain Res 2000;107(1-2):171-5. [DOI] [PubMed]
- 163.Berger N, Vaillancourt C, Boksa P. Genetic factors modulate effects of C-section birth on dopaminergic function in the rat. Neuroreport 2000;11(3):639-43. [DOI] [PubMed]
- 164.Fuster JM. The prefrontal cortex: anatomy, physiology and neuropsychology of the frontal lobe. New York: Raven Press; 1989.
- 165.Levin HS, Eisenberg HM, Benton AL. Frontal lobe and dysfunction. Oxford: Oxford University Press; 1991.
- 166.Weinberger DR, Berman KF, Zec RF. Physiologic dysfunction of dorsolateral prefrontal cortex in schizophrenia. I. Regional cerebral blood flow evidence. Arch Gen Psychiatry 1986;43(2):114-24. [DOI] [PubMed]
- 167.Weinberger DR, Berman KF, Illowsky BP. Physiological dysfunction of dorsolateral prefrontal cortex in schizophrenia. III. A new cohort and evidence for a monoaminergic mechanism. Arch Gen Psychiatry 1988;45(7):609-15. [DOI] [PubMed]
- 168.Pycock CJ, Kerwin RW, Carter CJ. Effect of lesion of cortical dopamine terminals on subcortical dopamine receptors in rats. Nature 1980;286:74-6. [DOI] [PubMed]
- 169.Le Moal M, Simon H. Mesocorticolimbic dopaminergic network: functional and regulatory roles. Physiol Rev 1991;71(1):155-234. [DOI] [PubMed]
- 170.Jaskiw GE, Karoum FK, Weinberger DR. Persistent elevations in dopamine and its metabolites in the nucleus accumbens after mild subchronic stress in rats with ibotenic acid lesions of the medial prefrontal cortex. Brain Res 1990;534(1-2):321-3. [DOI] [PubMed]
- 171.Jaskiw GE, Weinberger DR. Ibotenic acid lesions of medial prefrontal cortex augment swim-stress-induced locomotion. Pharmacol Biochem Behav 1992;41(3):607-9. [DOI] [PubMed]
- 172.Braun AR, Jaskiw GE, Vladar K, Sexton RH, Kolachana BS, Weinberger DR. Effects of ibotenic acid lesion of the medial prefrontal cortex on dopamine agonist-related behaviors in the rat. Pharmacol Biochem Behav 1993;46(1):51-60. [DOI] [PubMed]
- 173.Jaskiw GE, Karoum F, Freed WJ, Phillips I, Kleinman JE, Weinberger DR. Effect of ibotenic acid lesions of the medial prefrontal cortex on amphetamine-induced locomotion and regional brain catecholamine concentrations in the rat. Brain Res 1990;534(1-2):263-72. [DOI] [PubMed]
- 174.Lipska BK, Jaskiw GE, Braun AR, Weinberger DR. Prefrontal cortical and hippocampal modulation of haloperidol-induced catalepsy and apomorphine-induced stereotypic behaviors in the rat. Biol Psychiatry 1995;38(4):255-62. [DOI] [PubMed]
- 175.Whishaw IQ, Fiorino D, Mittleman G, Castaneda E. Do forebrain structures compete for behavioral expression? Evidence from amphetamine-induced behavior, microdialysis, and caudate-accumbens lesions in medial frontal cortex damaged rats. Brain Res 1992;576(1):1-11. [DOI] [PubMed]
- 176.Swerdlow NR, Lipska BK, Weinberger DR, Braff DL, Jaskiw GE, Geyer MA. Increased sensitivity to the sensorimotor gating-disruptive effects of apomorphine after lesions of medial prefrontal cortex or ventral hippocampus in adult rats. Psychopharmacology (Berl) 1995;122(1):27-34. [DOI] [PubMed]
- 177.Sesack SR, Pickel VM. In the rat medial nucleus accumbens, hippocampal and catecholaminergic terminals converge on spiny neurons and are in apposition to each other. Brain Res 1990;527(2):266-79. [DOI] [PubMed]
- 178.Mittleman G, LeDuc PA, Whishaw IQ. The role of D1 and D2 receptors in the heightened locomotion induced by direct and indirect dopamine agonists in rats with hippocampal damage: an animal analogue of schizophrenia. Behav Brain Res 1993; 55(2):253-67. [DOI] [PubMed]
- 179.Lipska BK, Jaskiw GE, Karoum F, Phillips I, Kleinman JE, Weinberger DR. Dorsal hippocampal lesion does not affect dopaminergic indices in the basal ganglia. Pharmacol Biochem Behav 1991;40:181-4. [DOI] [PubMed]
- 180.Whishaw IQ, Mittleman G. Hippocampal modulation of nucleus accumbens: behavioral evidence from amphetamine-induced activity profiles. Behav Neural Biol 1991;55(3):289-306. [DOI] [PubMed]
- 181.Lipska BK, Jaskiw GE, Chrapusta S, Karoum F, Weinberger DR. Ibotenic acid lesion of the ventral hippocampus differentially affects dopamine and its metabolites in the nucleus accumbens and prefrontal cortex in the rat. Brain Res 1992;585(1-2):1-6. [DOI] [PubMed]
- 182.Mittleman G, Bratt AM, Chase R. Heterogeneity of the hippocampus: effects of subfield lesions on locomotion elicited by dopaminergic agonists. Behav Brain Res 1998;92(1):31-45. [DOI] [PubMed]
- 183.Lipska BK, Jaskiw GE, Weinberger DR. Postpubertal emergence of hyperresponsiveness to stress and to amphetamine after neonatal excitotoxic hippocampal damage: a potential animal model of schizophrenia. Neuropsychopharmacology 1993; 9(1):67-75. [DOI] [PubMed]
- 184.Csernansky JG, Csernansky CA, Kogelman L, Montgomery EM, Bardgett ME. Progressive neurodegeneration after intracerebroventricular kainic acid administration in rats: implications for schizophrenia? Biol Psychiatry 1998;44(11):1143-50. [DOI] [PubMed]
- 185.Bardgett ME, Jackson JL, Taylor GT, Csernansky JG. Kainic acid decreases hippocampal neuronal number and increases dopamine receptor binding in the nucleus accumbens: an animal model of schizophrenia. Behav Brain Res 1995;70(2):153-64. [DOI] [PubMed]
- 186.Bardgett ME, Jacobs PS, Jackson JL, Csernansky JG. Kainic acid lesions enhance locomotor responses to novelty, saline, amphetamine, and MK-801. Behav Brain Res 1997;84(1-2):47-55. [DOI] [PubMed]
- 187.Andreasen NC, Arndt S, Swayze V, Cizadlo T, Flaum M, O'Leary D, et al. Thalamic abnormalities in schizophrenia visualized through magnetic resonance image averaging. Science 1994;266:294-8. [DOI] [PubMed]
- 188.Early TS, Reiman EM, Raichle ME, Spitznagel EL. Left globus pallidus abnormality in never-medicated patients with schizophrenia. Proc Natl Acad Sci U S A 1987;84(2):561-3. [DOI] [PMC free article] [PubMed]
- 189.Pakkenberg B. The volume of the mediodorsal thalamic nucleus in treated and untreated schizophrenics. Schizophr Res 1992;7(2):95-100. [DOI] [PubMed]
- 190.Kelsoe JR Jr, Cadet JL, Pickar D, Weinberger DR. Quantitative neuroanatomy in schizophrenia. A controlled magnetic resonance imaging study. Arch Gen Psychiatry 1988;45(6):533-41. [DOI] [PubMed]
- 191.Seidman LJ, Faraone SV, Goldstein JM, Goodman JM, Kremen WS, Matsuda G, et al. Reduced subcortical brain volumes in nonpsychotic siblings of schizophrenic patients: a pilot magnetic resonance imaging study. Am J Med Genet 1997;74(5):507-14. [DOI] [PubMed]
- 192.Kodsi MH, Swerdlow NR. Regulation of prepulse inhibition by ventral pallidal projections. Brain Res Bull 1997;43(2):219-28. [DOI] [PubMed]
- 193.Goldman PS. Functional development of the prefrontal cortex in early life and the problem of neuronal plasticity. Exp Neurol 1971;32(3):366-87. [DOI] [PubMed]
- 194.Stevens JR. Abnormal reinnervation as a basis for schizophrenia: a hypothesis. Arch Gen Psychiatry 1992;49(3):238-43. [DOI] [PubMed]
- 195.Flores G, Wood GK, Liang JJ, Quirion R, Srivastava LK. Enhanced amphetamine sensitivity and increased expression of dopamine D2 receptors in postpubertal rats after neonatal excitotoxic lesions of the medial prefrontal cortex. J Neurosci 1996;16(22):7366-75. [DOI] [PMC free article] [PubMed]
- 196.Brake WG, Flores G, Francis D, Meaney MJ, Srivastava LK, Gratton A. Enhanced nucleus accumbens dopamine and plasma corticosterone stress responses in adult rats with neonatal excitotoxic lesions to the medial prefrontal cortex. Neuroscience 2000;96(4):687-95. [DOI] [PubMed]
- 197.Lipska BK, al Amin HA, Weinberger DR. Excitotoxic lesions of the rat medial prefrontal cortex. Effects on abnormal behaviors associated with neonatal hippocampal damage. Neuropsychopharmacology 1998;19(6):451-64. [DOI] [PubMed]
- 198.Flores G, Barbeau D, Quirion R, Srivastava LK. Decreased binding of dopamine D3 receptors in limbic subregions after neonatal bilateral lesion of rat hippocampus. J Neurosci 1996; 16(6):2020-6. [DOI] [PMC free article] [PubMed]
- 199.Lipska BK, Chrapusta SJ, Egan MF, Weinberger DR. Neonatal excitotoxic ventral hippocampal damage alters dopamine response to mild repeated stress and to chronic haloperidol. Synapse 1995;20(2):125-30. [DOI] [PubMed]
- 200.Brake WG, Sullivan RM, Flores G, Srivastava LK, Gratton A. Neonatal ventral hippocampal lesions attenuate the nucleus accumbens dopamine response to stress: an electrochemical study in the adult rat. Brain Res 1999;831(1-2):25-32. [DOI] [PubMed]
- 201.Lipska BK, Weinberger DR. Delayed effects of neonatal hippocampal damage on haloperidol-induced catalepsy and apomorphine-induced stereotypic behaviors in the rat. Brain Res Dev Brain Res 1993;75(2):213-22. [DOI] [PubMed]
- 202.Davis M, Mansbach RS, Swerdlow NR, Campeau S, Braff DL, Geyer MA. Apomorphine disrupts the inhibition of acoustic startle induced by weak prepulses in rats. Psychopharmacology (Berl) 1990;102(1):1-4. [DOI] [PubMed]
- 203.Swerdlow NR, Braff DL, Masten VL, Geyer MA. Schizophrenic-like sensorimotor gating abnormalities in rats following dopamine infusion into the nucleus accumbens. Psychopharmacology (Berl) 1990;101(3):414-20. [DOI] [PubMed]
- 204.Swerdlow NR, Mansbach RS, Geyer MA, Pulvirenti L, Koob GF, Braff DL. Amphetamine disruption of prepulse inhibition of acoustic startle is reversed by depletion of mesolimbic dopamine. Psychopharmacology (Berl) 1990;100(3):413-6. [DOI] [PubMed]
- 205.Grecksch G, Bernstein HG, Becker A, Hollt V, Bogerts B. Disruption of latent inhibition in rats with postnatal hippocampal lesions. Neuropsychopharmacology 1999;20(6):525-32. [DOI] [PubMed]
- 206.Sams-Dodd F, Lipska BK, Weinberger DR. Neonatal lesions of the rat ventral hippocampus result in hyperlocomotion and deficits in social behaviour in adulthood. Psychopharmacology (Berl) 1997;132(3):303-10. [DOI] [PubMed]
- 207.Becker A, Grecksch G, Bernstein HG, Hollt V, Bogerts B. Social behaviour in rats lesioned with ibotenic acid in the hippocampus: quantitative and qualitative analysis. Psychopharmacology (Berl) 1999;144(4):333-8. [DOI] [PubMed]
- 208.Bachevalier J, Alvarado MC, Malkova L. Memory and socioemotional behavior in monkeys after hippocampal damage incurred in infancy or in adulthood. Biol Psychiatry 1999;46(3):329-39. [DOI] [PubMed]
- 209.Beauregard M, Bachevalier J. Neonatal insult to the hippocampal region and schizophrenia: a review and a putative animal model. Can J Psychiatry 1996;41(7):446-56. [DOI] [PubMed]
- 210.Montgomery EM, Bardgett ME, Lall B, Csernansky CA, Csernansky JG. Delayed neuronal loss after administration of intracerebroventricular kainic acid to preweanling rats. Brain Res Dev Brain Res 1999;112(1):107-16. [DOI] [PubMed]
- 211.Juraska JM. Sex differences in “cognitive” regions of the rat brain. Psychoneuroendocrinology 1991;16(1-3):105-9. [DOI] [PubMed]
- 212.Jaskiw GE, Weinberger DR. Ibotenic acid lesions of the medial prefrontal cortex potentiate FG-7142-induced attenuation of exploratory activity in the rat. Pharmacol Biochem Behav 1990; 36(3):695-7. [DOI] [PubMed]
- 213.Deutch AY, Roth RH. The determinants of stress-induced activation of the prefrontal cortical dopamine system. Prog Brain Res 1990;85:367-402. [DOI] [PubMed]
- 214.Kalsbeek A, Voorn P, Buijs RM, Pool CW, Uylings HB. Development of the dopaminergic innervation in the prefrontal cortex of the rat. J Comp Neurol 1988;269(1):58-72. [DOI] [PubMed]
- 215.Schroeder H, Grecksch G, Becker A, Bogerts B, Hoellt V. Alterations of the dopaminergic and glutamatergic neurotransmission in adult rats with postnatal ibotenic acid hippocampal lesion. Psychopharmacology (Berl) 1999;145(1):61-6. [DOI] [PubMed]
- 216.Bernstein HG, Grecksch G, Becker A, Hollt V, Bogerts B. Cellular changes in rat brain areas associated with neonatal hippocampal damage. Neuroreport 1999;10(11):2307-11. [DOI] [PubMed]
- 217.Lillrank SM, Lipska BK, Kolachana BS, Weinberger DR. Attenuated extracellular dopamine levels after stress and amphetamine in the nucleus accumbens of rats with neonatal ventral hippocampal damage. J Neural Transm 1999;106(2):183-96. [DOI] [PubMed]
- 218.Wan RQ, Giovanni A, Kafka SH, Corbett R. Neonatal hippocampal lesions induced hyperresponsiveness to amphetamine: behavioral and in vivo microdialysis studies. Behav Brain Res 1996;78(2):211-23. [DOI] [PubMed]
- 219.Saunders RC, Kolachana BS, Bachevalier J, Weinberger DR. Neonatal lesions of the medial temporal lobe disrupt prefrontal cortical regulation of striatal dopamine. Nature 1998; 393:169-71. [DOI] [PubMed]
- 220.Wan RQ, Corbett R. Enhancement of postsynaptic sensitivity to dopaminergic agonists induced by neonatal hippocampal lesions. Neuropsychopharmacology 1997;16(4):259-68. [DOI] [PubMed]
- 221.Lillrank SM, Lipska BK, Weinberger DR, Fredholm BB, Fuxe K, Ferre S. Adenosine and dopamine receptor antagonist binding in the rat ventral and dorsal striatum: lack of changes after a neonatal bilateral lesion of the ventral hippocampus. Neurochem Int 1999;34(3):235-44. [DOI] [PubMed]
- 222.Kennard MA. Age and other factors in motor recovery from precentral lesion in monkeys. Am J Physiol 1936;115:138-46.
- 223.Kolb B, Whishaw IQ. Plasticity in the neocortex: mechanisms underlying recovery from early brain damage. Prog Neurobiol 1989;32(4):235-76. [DOI] [PubMed]
- 224.Kolb B, Gibb R. Sparing of function after neonatal frontal lesions correlates with increased cortical dendritic branching: a possible mechanism for the Kennard effect. Behav Brain Res 1991;43(1):51-6. [DOI] [PubMed]
- 225.Rice D, Barone S Jr. Critical periods of vulnerability for the developing nervous system: evidence from humans and animal models. Environ Health Perspect 2000;108(Suppl 3):511-33. [DOI] [PMC free article] [PubMed]
- 226.Ikonomidou C, Bosch F, Miksa M, Bittigau P, Vockler J, Dikranian K, et al. Blockade of NMDA receptors and apoptotic neurodegeneration in the developing brain. Science 1999;283:70-4. [DOI] [PubMed]
- 227.Catsicas S, Grenningloh G, Pich EM. Nerve-terminal proteins: to fuse to learn. Trends Neurosci 1994;17(9):368-73. [DOI] [PubMed]
- 228.Greengard P, Valtorta F, Czernik AJ, Benfenati F. Synaptic vesicle phosphoproteins and regulation of synaptic function. Science 1993;259:780-5. [DOI] [PubMed]
- 229.Berke JD, Hyman SE. Addiction, dopamine, and the molecular mechanisms of memory. Neuron 2000;25(3):515-32. [DOI] [PubMed]
- 230.Tcherepanov AA, Sokolov BP. Age-related abnormalities in expression of mRNAs encoding synapsin 1A, synapsin 1B, and synaptophysin in the temporal cortex of schizophrenics. J Neurosci Res 1997;49(5):639-44. [DOI] [PubMed]
- 231.Browning MD, Dudek EM, Rapier JL, Leonard S, Freedman R. Significant reductions in synapsin but not synaptophysin specific activity in the brains of some schizophrenics. Biol Psychiatry 1993;34(8):529-35. [DOI] [PubMed]
- 232.Grebb JA, Greengard P. An analysis of synapsin II, a neuronal phosphoprotein, in postmortem brain tissue from alcoholic and neuropsychiatrically ill adults and medically ill children and young adults. Arch Gen Psychiatry 1990;47(12):1149-56. [DOI] [PubMed]
- 233.Eastwood SL, Burnet PW, Harrison PJ. Altered synaptophysin expression as a marker of synaptic pathology in schizophrenia. Neuroscience 1995;66(2):309-19. [DOI] [PubMed]
- 234.Karson CN, Mrak RE, Schluterman KO, Sturner WQ, Sheng JG, Griffin WS. Alterations in synaptic proteins and their encoding mRNAs in prefrontal cortex in schizophrenia: a possible neurochemical basis for ‘hypofrontality.’ Mol Psychiatry 1999;4(1):39-45. [DOI] [PubMed]
- 235.Glantz LA, Lewis DA. Reduction of synaptophysin immunoreactivity in the prefrontal cortex of subjects with schizophrenia. Regional and diagnostic specificity. Arch Gen Psychiatry 1997;54(10):943-52. [DOI] [PubMed]
- 236.Stober G, Meyer J, Nanda I, Wienker TF, Saar K, Knapp M, et al. Linkage and family-based association study of schizophrenia and the synapsin III locus that maps to chromosome 22q13. Am J Med Genet 2000;96(3):392-7. [DOI] [PubMed]
- 237.Ohtsuki T, Ichiki R, Toru M, Arinami T. Mutational analysis of the synapsin III gene on chromosome 22q12-q13 in schizophrenia. Psychiatry Res 2000;94(1):1-7. [DOI] [PubMed]
- 238.Ohmori O, Shinkai T, Hori H, Kojima H, Nakamura J. Synapsin III gene polymorphisms and schizophrenia. Neurosci Lett 2000;279(2):125-7. [DOI] [PubMed]
- 239.Walsh FS, Doherty P. Neural cell adhesion molecules of the immunoglobulin superfamily: role in axon growth and guidance. Annu Rev Cell Dev Biol 1997;13:425-56. [DOI] [PubMed]
- 240.Tear G. Molecular cues that guide the development of neural connectivity. Essays Biochem 1998;33:1-13. [DOI] [PubMed]
- 241.Kamiguchi H, Hlavin ML, Yamasaki M, Lemmon V. Adhesion molecules and inherited diseases of the human nervous system. Annu Rev Neurosci 1998;21:97-125. [DOI] [PubMed]
- 242.Cremer H, Chazal G, Goridis C, Represa A. NCAM is essential for axonal growth and fasciculation in the hippocampus. Mol Cell Neurosci 1997;8(5):323-35. [DOI] [PubMed]
- 243.Seki T, Rutishauser U. Removal of polysialic acid-neural cell adhesion molecule induces aberrant mossy fiber innervation and ectopic synaptogenesis in the hippocampus. J Neurosci 1998;18(10):3757-66. [DOI] [PMC free article] [PubMed]
- 244.Barbeau D, Liang JJ, Robitalille Y, Quirion R, Srivastava LK. Decreased expression of the embryonic form of the neural cell adhesion molecule in schizophrenic brains. Proc Natl Acad Sci U S A 1995;92(7):2785-9. [DOI] [PMC free article] [PubMed]
- 245.Tomasiewicz H, Ono K, Yee D, Thompson C, Goridis C, Rutishauser U, et al. Genetic deletion of a neural cell adhesion molecule variant (N-CAM-180) produces distinct defects in the central nervous system. Neuron 1993;11(6):1163-74. [DOI] [PubMed]
- 246.Wood GK, Tomasiewicz H, Rutishauser U, Magnuson T, Quirion R, Rochford J, et al. NCAM-180 knockout mice display increased lateral ventricle size and reduced prepulse inhibition of startle. Neuroreport 1998;9(3):461-6. [DOI] [PubMed]
- 247.Walsh CA. Genetics of neuronal migration in the cerebral cortex. Ment Retard Dev Disabil Res Rev 2000;6(1):34-40. [DOI] [PubMed]
- 248.Lambert DR, Goffinet AM. A new view of early cortical development. Biochem Pharmacol 1998;56(11):1403-9. [DOI] [PubMed]
- 249.D'Arcangelo G, Curran T. Reeler: new tales on an old mutant mouse. Bioessays 1998;20(3):235-44. [DOI] [PubMed]
- 250.Impagnatiello F, Guidotti AR, Pesold C, Dwivedi Y, Caruncho H, Pisu MG, et al. A decrease of reelin expression as a putative vulnerability factor in schizophrenia. Proc Natl Acad Sci U S A 1998;95(26):15718-23. [DOI] [PMC free article] [PubMed]
- 251.Fatemi SH, Emamian ES, Kist D, Sidwell RW, Nakajima K, Akhter P, et al. Defective corticogenesis and reduction in Reelin immunoreactivity in cortex and hippocampus of prenatally infected neonatal mice. Mol Psychiatry 1999;4(2):145-54. [DOI] [PubMed]
- 252.Saueressig H, Burrill J, Goulding M. Engrailed-1 and netrin-1 regulate axon pathfinding by association interneurons that project to motor neurons. Development 1999;126(19):4201-12. [DOI] [PubMed]
- 253.Hopker VH, Shewan D, Tessier-Lavigne M, Poo M, Holt C. Growth-cone attraction to netrin-1 is converted to repulsion by laminin-1. Nature 1999;401:69-73. [DOI] [PubMed]
- 254.Richards LJ, Koester SE, Tuttle R, O'Leary DD. Directed growth of early cortical axons is influenced by a chemoattractant released from an intermediate target. J Neurosci 1997;17(7):2445-58. [DOI] [PMC free article] [PubMed]
- 255.Wang H, Copeland NG, Gilbert DJ, Jenkins NA, Tessier-Lavigne M. Netrin-3, a mouse homolog of human NTN2L, is highly expressed in sensory ganglia and shows differential binding to netrin receptors. J Neurosci 1999;19(12):4938-47. [DOI] [PMC free article] [PubMed]
- 256.Deiner MS, Sretavan DW. Altered midline axon pathways and ectopic neurons in the developing hypothalamus of netrin-1- and DCC-deficient mice. J Neurosci 1999;19(22):9900-12. [DOI] [PMC free article] [PubMed]
- 257.Gale NW, Yancopoulos GD. Ephrins and their receptors: a repulsive topic? Cell Tissue Res 1997;290(2):227-41. [DOI] [PubMed]
- 258.Holder N, Klein R. Eph receptors and ephrins: effectors of morphogenesis. Development 1999;126(10):2033-44. [DOI] [PubMed]
- 259.O'Leary DD, Wilkinson DG. Eph receptors and ephrins in neural development. Curr Opin Neurobiol 1999;9(1):65-73. [DOI] [PubMed]
- 260.Eberhart J, Swartz M, Koblar SA, Pasquale EB, Tanaka H, Krull CE. Expression of EphA4, ephrin-A2 and ephrin-A5 during axon outgrowth to the hindlimb indicates potential roles in pathfinding. Dev Neurosci 2000;22(3):237-50. [DOI] [PubMed]
- 261.Stein E, Savaskan NE, Ninnemann O, Nitsch R, Zhou R, Skutella T. A role for the Eph ligand ephrin-A3 in entorhino-hippocampal axon targeting. J Neurosci 1999;19(20):8885-93. [DOI] [PMC free article] [PubMed]
- 262.Yue Y, Su J, Cerretti DP, Fox GM, Jing S, Zhou R. Selective inhibition of spinal cord neurite outgrowth and cell survival by the Eph family ligand ephrin-A5. J Neurosci 1999;19(22):10026-35. [DOI] [PMC free article] [PubMed]
- 263.Yue Y, Widmer DA, Halladay AK, Cerretti DP, Wagner GC, Dreyer JL, et al. Specification of distinct dopaminergic neural pathways: roles of the Eph family receptor EphB1 and ligand ephrin-B2. J Neurosci 1999;19(6):2090-101. [DOI] [PMC free article] [PubMed]
- 264.Dutting D, Handwerker C, Drescher U. Topographic targeting and pathfinding errors of retinal axons following overexpression of ephrinA ligands on retinal ganglion cell axons. Dev Biol 1999;216(1):297-311. [DOI] [PubMed]
- 265.Hornberger MR, Dutting D, Ciossek T, Yamada T, Handwerker C, Lang S, et al. Modulation of EphA receptor function by coexpressed ephrinA ligands on retinal ganglion cell axons. Neuron 1999;22(4):731-42. [DOI] [PubMed]
- 266.Kolodkin AL. Semaphorin-mediated neuronal growth cone guidance. Prog Brain Res 1998;117:115-32. [DOI] [PubMed]
- 267.Roskies AL. Dissecting semaphorin signaling. Neuron 1998; 21(5):935-6. [DOI] [PubMed]
- 268.Bagnard D, Lohrum M, Uziel D, Puschel AW, Bolz J. Semaphorins act as attractive and repulsive guidance signals during the development of cortical projections. Development 1998; 125(24):5043-53. [DOI] [PubMed]
- 269.de Castro F, Hu L, Drabkin H, Sotelo C, Chedotal A. Chemoattraction and chemorepulsion of olfactory bulb axons by different secreted semaphorins. J Neurosci 1999;19(11):4428-36. [DOI] [PMC free article] [PubMed]
- 270.Wong JT, Wong ST, O'Connor TP. Ectopic semaphorin-1a functions as an attractive guidance cue for developing peripheral neurons. Nat Neurosci 1999;2(9):798-803. [DOI] [PubMed]
- 271.Polleux F, Morrow T, Ghosh A. Semaphorin 3A is a chemoattractant for cortical apical dendrites. Nature 2000;404:567-73. [DOI] [PubMed]
- 272.Fujisawa H, Kitsukawa T. Receptors for collapsin/semaphorins. Curr Opin Neurobiol 1998;8(5):587-92. [DOI] [PubMed]
- 273.Yu HH, Kolodkin AL. Semaphorin signaling: a little less per-plexin. Neuron 1999;22(1):11-4. [DOI] [PubMed]
- 274.Kendler KS, MacLean CJ, O'Neill FA, Burke J, Murphy B, Duke F, et al. Evidence for a schizophrenia vulnerability locus on chromosome 8p in the Irish Study of High-Density Schizophrenia Families. Am J Psychiatry 1996;153(12):1534-40. [DOI] [PubMed]
- 275.Pulver AE. Search for schizophrenia susceptibility genes. Biol Psychiatry 2000;47(3):221-30. [DOI] [PubMed]