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. Author manuscript; available in PMC: 2009 Sep 1.
Published in final edited form as: Epilepsia. 2009 Aug;50(Suppl 7):37–42. doi: 10.1111/j.1528-1167.2009.02217.x

The epileptic hypothesis: developmentally related arguments based on animal models

Aristea S Galanopoulou 1,2, Solomon L Moshé 1,3
PMCID: PMC2736106  NIHMSID: NIHMS139570  PMID: 19682049

Summary

The significant morbidity linked to epileptic encephalopathies of childhood has prompted the need to identify and dissect the factors and mechanisms that contribute to the resultant functional regression. Although experiments specifically assessing language in rodents are difficult to design, a number of studies have shed light on the conditions that contribute to the functional deterioration. In particular, interictal spikes and seizures, especially if prolonged or frequent, may cause acute or long-lasting effects on brain functioning and development, which may impair performance in a variety of behavioral tests. These effects are further modified by a number of genetic, biological and epigenetic factors, including age, sex, and underlying pathology, that further diversify outcome. Of special importance is the developmental age when the epileptic disorder manifests, because it may dictate outcome but also may be a deciding factor in selecting appropriate therapies.

Keywords: GABA, catastrophic epilepsies, substantia nigra, status epilepticus, infantile spasms

It is an interesting proposition to explain the deficits in Landau Kleffner Syndrome (Landau & Kleffner 1957). The majority of children with Landau Kleffner syndrome (60%) have seizures as a first symptom whereas the cardinal feature of this condition is the prominent interictal epileptiform activity (Galanopoulou, et al. 2000). It would have been very nice to be able to develop specific arguments based on animal models to discern the specific impacts of the acute effects of the epileptiform activities versus their long-lasting sequelae on brain development and function. However, there are many limitations in that the Landau Kleffner syndrome mainly deals with abnormalities in language which is very difficult to test in animal models. Nevertheless, there are several studies suggesting that epileptiform discharges may have detrimental effects on behavior and cognition as best as it can be tested in animals.

Most of the animal studies to date have been performed in rats. To understand the meaning of the studies, it is important to have a comparative relationship of human ages to rat lifespan. The rat is born prematurely, therefore, a 7-8 day old rat is considered equivalent to a human newborn at least in terms of rate of growth of the brain (Gottlieb, et al. 1977;Dobbing & Sands 1979;Ojeda 1994;Avishai-Eliner, et al. 2002;Velisek & Moshé 2002). There are many other parameters that cannot be accurately depicted as equivalent between a 7-8 day old rat to a human newborn, but this approximation will suffice for the current state of the art. The next major milestone in the rat is when it reaches adolescence and this is approximately around the 5th week of life. This means that from postnatal days (PN) 7-8 to PN35 the rat will undergo major changes in development that will be equivalent to human infants, toddlers, and prepubescent children. Finally, the rat reaches adulthood somewhere around PN60 and senescence about two years of age of age. In this presentation we will discuss first the effects of spikes, second the effects of status epilepticus, third the effects of repetitive seizures, and fourth the available models of catastrophic epilepsies.

Effects of interictal epileptiform discharges

There is not much information regarding the effects of spikes on brain function and development. Holmes and his co-workers have studied the role of interictal epileptiform abnormalities in cognitive impairment. Most of the studies were performed in adult animals and suggest that epileptiform discharges in older age groups can impair cognitive abilities through interference with awake learning, and memory, as well as memory consolidation during sleep (Holmes & Lenck-Santini 2006;Shatskikh, et al. 2006;Zhou, et al. 2007). The effects appear to be more pronounced if the spikes are very frequent and widespread. In a series of elegant studies, Holmes and co-workers showed that the electrical induction of spikes in the hippocampus impairs recognition and spatial memory in rats by disrupting the ability of hippocampal place cells to recognize the position of the animal (Shatskikh et al. 2006;Zhou et al. 2007).

A very interesting study by Chow and associates describes the generation of penicillin- and bicuculline-induced epileptiform discharges in the striate cortex of rabbits and their impact on the formation of the visual receptive fields of the lateral geniculate nucleus (Chow, et al. 1978;Ostrach, et al. 1984). These investigators showed that when aqueous penicillin or bicuculline were injected twice daily into a cannula implanted over the monocular area of the visual cortex from PN8-9 and continued until PN24-30, interictal epileptiform discharges were routinely observed only from the cortical site of the injections. These discharges hindered the appearance of complex and oriented-directional type cells at the lateral geniculate nucleus which may suggest epileptogenic disruption of organized geniculostriate activity. These effects were age-specific, as they were not observed in similarly treated adult rabbits (Baumbach & Chow 1981).

Effects of early life seizures and status epilepticus

The effects of seizures and status epilepticus in normal developing rodents have been extensively described. Again, here there appears to be an age-related effect. However, it should be emphasized that most of the studies have been performed in male rats or mice and the issue of strain or gender-specific genetic factors has not been extensively studied. It is generally accepted that status epilepticus in normal developing rats does not usually induce hippocampal cell loss or synaptic reorganization in the dentate gyrus unless it is induced after the second postnatal week and the extent of injury increases with age (Albala, et al. 1984;Cavalheiro, et al. 1987;Sperber, et al. 1992;Holmes & Ben-Ari 1998;Sankar, et al. 1998;Sankar, et al. 2000;Haas, et al. 2001;Cilio, et al. 2003;Raol, et al. 2003). When injury occurs, its severity and associated patterns differ among models of seizures (Sankar et al. 2000;Cilio et al. 2003). For instance, following lithium-pilocarpine induced SE in two-week old rats, cell loss occurs mostly at the CA1 region, whereas if status epilepticus is induced in 3-4 week old rats, injury shifts from the CA1 towards the CA3 and dentate granular areas (Sankar et al. 2000). In occasional models, like the corticotropin releasing hormone (CRH) induced status epilepticus, hippocampal injury has been reported in 10-12 day old pups after SE (Ribak & Baram 1996). Predisposing factors, like the pro-inflammatory reagent lipopolysaccharide also facilitate or augment the status epilepticus-induced injury in neonatal rats (Sankar, et al. 2007).

Although status epilepticus early in life produces acute changes in terms of metabolic disturbances, it does not necessarily increase the probability to manifest spontaneous seizures later in life (Okada, et al. 1984;Stafstrom, et al. 1993;Santos, et al. 2000;Roch, et al. 2002;Raol et al. 2003;Kubova, et al. 2004;Raffo, et al. 2004;Galanopoulou 2008). When spontaneous seizures are recorded, they are few (dos Santos, et al. 2000;Raol et al. 2003;Kubova et al. 2004). This is dramatically different from the effects of equivalent or even less severe status epilepticus in adult animals, in which the propensity to develop epilepsy is almost a hundred percent after status epilepticus. Early life status epilepticus may cause long-lasting disruption in learning and memory and other behaviors but to a much lesser degree than if it occurs in older animals (Stafstrom et al. 1993;Lynch, et al. 2000;Kubova et al. 2004;Sayin, et al. 2004). The resultant cognitive dysfunction may not necessarily require the presence of hippocampal cell loss or interictal spikes (Lee, et al. 2001). Liu et al. induced status epilepticus in PN20 rats and studied the place cells at PN70 (Liu, et al. 2003). They found that the early history of status epilepticus was associated with decreased place cell precision (decreased coherence) and stability, which paralleled the deficits in water maze performance during adulthood. Data on animals exposed to status epilepticus at an earlier age are lacking.

Among the factors that determine outcome is the seizure load and postnatal age. Isolated or rare brief seizures do not seem to cause as much disruption as the frequent or prolonged seizures. For instance, unlike the effects of status epilepticus, a single flurothyl-induced seizure only transiently disrupted the function of the place cells (Liu et al. 2003). Fifteen flurothyl-induced brief seizures during the first 5 days of life decreased the amplitude of inhibitory GABAA-mediated inhibitory postsynaptic currents in PN15-17 rats without affecting glutamatergic resposes (Isaeva, et al. 2006). In contrast, more than 15 brief flurothyl seizures were required to alter the expression of NMDA receptor subunit NR2A in PN9-13 C57BL/6 mice, but this effect was not observed in adults (Swann, et al. 2007). A cluster of neonatal seizures induced by a single kainic acid injection at PN7 altered glutamatergic synapses in adulthood, as a consequence of altering normal development (Cornejo, et al. 2007).

However, strain and model-specific differences in hippocampal changes have been observed which may reflect the role of genetic and epigenetic modifiers. These could also influence the ability to elicit neuroinflammatory responses which may alter outcome (Vezzani, et al. 2002;Borges, et al. 2003;Xu, et al. 2004;Ravizza, et al. 2005;Sankar et al. 2007;Winawer, et al. 2007). Identifying and elucidating the role of these modifiers may be crucial in selecting those specific children that may have a likelihood of developing severe consequences following status epilepticus.

The effects of repetitive seizures are also worthwhile. Multiple pilocarpine-induced episodes of status epilepticus in very young rats between 7 and 9 days of age are associated with the development of absence-like epilepsy later on (Ferreira, et al. 2003) and these rats show less exploratory activity as well as memory and learning problems (Santos et al. 2000). Neuroanatomical studies show no gross pathologic changes but there are progressive, subtle site-specific alterations of intracortical and hippocampal circuitries especially in the expression and the location of GABAergic neurons (da Silva, et al. 2005).

Effects of early life seizures on subcortical centers controlling seizures and cognition

In our studies, we investigated the effects of 3 episodes of kainic acid induced status epilepticus (3KA-SE) on the maturation of GABAAergic responses in the rat hippocampus and the substantia nigra pars reticulata (SNR). Both these structures are known to be involved not only in the control of seizures but also in cognition. The SNR is a crucial site involving the control of seizures as a function of age such that by PN30 the infusions of GABAergic agonists markedly delay the onset of flurothyl-induced seizures (Sperber, et al. 1989;Veliskova & Moshé 2001). The SNR also affects frontal cortical activity and working memory through its dynamic gating, produced by the inhibitory circuits (O’Reilly 2006). We specifically looked at how 3KA-SE affect the direction of GABAA responses, i.e. depolarizing versus hyperpolarizing, as this would re-define the patterns not only of interneuronal communications but also of neuronal differentiation. 3KA-SE were induced at a very young age (PN4-6) in rats of both sexes. GABAAergic synapses have already started to be formed by this young age, preceding the development of glutamatergic excitatory synapses (Ben-Ari 2001). Most importantly, in newborn rats, GABAAergic currents are depolarizing in most studied neurons, due to the low levels of the chloride cotransporter KCC2 relative to NKCC1 (Plotkin, et al. 1997;Rivera, et al. 1999;Galanopoulou, et al. 2003;Galanopoulou 2008). The depolarizing GABAAergic currents control neuronal development by promoting calcium entry into the cell through voltage-sensitive calcium channels (Ben-Ari 2002). As a result, a number of calcium-sensitive signaling processes are activated and control cellular proliferation, migration, neuronal differentiation, synaptic integration, as well as neuronal activity and plasticity (Ben-Ari 2002).

Three episodes of status epilepticus do not cause any acute neuronal injury but accelerate the switch of synaptic GABAAergic responses in both male and female rat SNR in a sex-specific fashion limiting the time that calcium dependent processes remain in effect (Galanopoulou et al. 2003;Kyrozis, et al. 2003). This disrupts the GABAAergic signaling of the SNR including the ability of GABAA receptor agonists to suppress seizures (Heida, et al. 2006) as well as the expression of the α1 GABAA receptor subunit at PN30 (Galanopoulou, et al. 2006). Such effects may further impair the ability to resist seizures or to respond to GABAA-acting antiepileptics that are commonly used in patients with epileptic encephalopathies.

Similarly, 3KA-SE also accelerate the appearance of hyperpolarizing GABAA responses in the male CA1 pyramidal region (Galanopoulou 2008). However the 3KA-SE effects are opposite in neurons that already have hyperpolarizing GABAA signaling at the time of seizures, like the female CA1 pyramidal neurons, suggesting that GABAA receptors may be one of the age and gender-specific modifiers of the effects of status epilepticus (Galanopoulou 2008). Further clarification of the sex-specific factors that may influence outcome in epileptic encephalopathies, like the Landau Kleffner syndrome, which show higher prevalence in boys (Bureau 1995;Galanopoulou et al. 2000) would be helpful to design better therapies.

Since evolution into epilepsy may potentially aggravate the effects of seizures on the cognitive reserve, one of the important goals is to predict under what circumstances epileptogenesis will ensue following status epilepticus early in life. The studies by Roch et al. suggest that magnetic resonance imaging obtained within 24-48 hours after the onset of status epilepticus may be predictive of the development of epilepsy later on as it shows transient magnetic resonance changes in T2 relaxation time in the pyriform cortex (Roch et al. 2002). These changes disappear after 48 hours but are indeed associated with the development of epilepsy later on. Numerous other studies have been performed and provided more insight into the in vivo biomarkers of epileptogenesis or cognitive dysfunction using electrophysiological or imaging mehods (Yu, et al. 2002;Sanchez, et al. 2006;Engelhorn, et al. 2007;Gomes, et al. 2007;Kharatishvili, et al. 2007;Immonen, et al. 2008). These have used diffusion weighted magnetic resonance imaging methods with or without electroencephalographic recordings to prospectively follow the evolution of neuronal loss and epileptogenesis (Engelhorn et al. 2007;Kharatishvili et al. 2007), spectroscopic imaging to identify early metabolic dysfunction during the latent phase of epileptogenesis (Gomes et al. 2007), manganese enhanced MRI to detect plastic changes, like axonal sprouting, in the epileptic hippocampus (Immonen et al. 2008). However, to extrapolate such findings in the early life epileptic encephalopathies, we will need to have appropriate animal models for such catastrophic epileptic encephalopathies as well as adequate in vivo methods to evaluate their impact on specialized cognitive functions, including language.

Models of catastrophic epileptic syndromes

More recently, models of catastrophic epilepsy have been developed. One such model has been described by Snead and colleague and represents an atypical absence/Lennox Gastaut model induced by the administration of the cholesterol inhibitor AY-9944 which creates a model of atypical absences (Chan, et al. 2004). Snead et al. developed a GABAB R1a subunit overexpressing transgenic mouse with altered expression of GABAB receptors and that specific mouse has an atypical absence phenotype (Wu, et al. 2007). In both models there are cognitive deficits and hippocampal dysfunction and it appears that the cognitive impairment is related to the abnormalities in the expression of GABAB receptors. However, the slow spike-and-wave discharges in both appear to be independent of the deteriorations of cognitive impairment, although further studies are needed. In addition, knockout mice with deletion at the β3 subunit of the GABAA receptors (GABRB3 (-/-)) have been developed and reproduce the epileptic phenotype with cognitive dysfunction of Angelman syndrome (DeLorey, et al. 1998). GABRB3 (+/-) heterozygous mice, also demonstrate the maternal type of genomic imprinting seen in this syndrome (Liljelund, et al. 2005).

A new rodent model of symptomatic infantile spasms has been created in our laboratory, by the application of a combination of lipopolysaccharide, doxorubicin into the brain and systemic administration of p-chloro-phenylalanine, that produce cortical and subcortical injury and serotonin depletion. In these pups, tremendous worsening in the behavior has been observed after the onset of epileptic spasms (Albert Einstein College of Medicine patent serial #: 60/900,487) (Scantlebury & Moshé 2006). Studies in this experimental model as well as the model described by Swann et al. and Velisek et al may provide new insights on how the epileptic process may affect brain development (Velisek, et al. 2007;Lee, et al. 2008).

Epigenetic factors may influence the impact of early life seizures

Seizures occurring during the sensitive early life formative period may also alter the functional maturation of the brain through epigenetic modifications. Repetitive seizures can pose a significant stress or lead to deprivation of normal environmental stimuli, which by itself may alter brain development. Baram’s group, using murine organotypic cultures of early postnatal hippocampi, has demonstrated that corticotropin releasing hormone (CRH), a stress mediator, may accelerate dendritic spine retraction in the hippocampus (Chen, et al. 2008). In rodents, early life maternal separation or handling can also trigger age-specific changes in dendritic spine development or GABAA receptor physiology (Hsu, et al. 2003;Bock, et al. 2005;Galanopoulou 2008). In contrast, environmental enrichment may reverse the adverse effects of early life seizures on exploratory behavior and the expression of genes involved in synaptic plasticity (Koh, et al. 2005). Such findings raise the optimism that certain aspects of the cognitive dysfunction observed in children with frequent seizures could potentially be reversible.

In summary, the effects of spikes, status epilepticus, or repetitive seizures are variable and they depend on the model that has been used, the age, sex, the presence or absence of underlying pathology, and the duration or severity of epileptic discharges. Indeed there appear to be developmental windows for the offset of these deficits. The vulnerability of the immature brain to epileptic events appears to stem more from the disruption of highly demanding developmental processes which are at their peak, like synaptogenesis, pruning, neuronal migration and differentiation, and to a lesser extent from neuronal death, a prominent consequence of seizures during the more mature stages of the development. Genetic influences and epigenetic alterations need to be further investigated to understand the changes that are observed following these conditions. The treatments then should be aimed against the factors responsible for the epileptiform discharges but also to prevent a specific functional deficit that may be caused by or associated with these epileptiform activities.

Acknowledgements

We would like to acknowledge the funding by NIH NINDS research grants NS20253, NS58303, and NS45243, as well as grants from PACE, the International Rett Syndrome Foundation, and the Heffer Family Foundation. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that their report is consistent with those guidelines. None of the authors has any conflict of interest to disclose. Dr. Moshé is the recipient of a Martin A. and Emily L. Fisher fellowship in Neurology & Pediatrics.

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