Schizophrenia in Translation: Disrupted in Schizophrenia (DISC1): Integrating Clinical and Basic Findings

Abstract

The disrupted in schizophrenia 1 (DISC1) gene has been linked to schizophrenia and other serious mental illnesses in multiple pedigrees. This article will review the neurobiology of DISC1 in normal developing and adult brain and the putative role of the mutant form in major mental illness, particularly schizophrenia. The initial genetic finding of an association between DISC1 and schizophrenia in a Scottish population has now been replicated in Finnish, American, Japanese, and Taiwanese populations. DISC1 is present throughout the brain of a variety of species during development and adulthood, including many of the brain regions known to be abnormal in schizophrenia, such as the prefrontal cortex, hippocampus, and thalamus. The functions of DISC1 in the developing brain include neuronal migration, neurite outgrowth, and neurite extension. In the adult, DISC1 has been identified in multiple populations of neurons and in structures associated with synaptic function, suggesting that one of its adult functions may be synaptic plasticity. DISC1 is associated with numerous cognitive functions that are abnormal in schizophrenia. Converging evidence from cell culture, mice mutants, postmortem brain, and genetics implicates mutant DISC1 in the pathophysiology of schizophrenia and other mental illnesses.

Introduction

Major mental illnesses such as schizophrenia, schizoaffective disorder, bipolar disorder, and major depression are complex and devastating diseases of the brain. These illnesses share in common certain symptoms, risk factors, and are undoubtedly produced by a combination of genetic and environmental causes. Schizophrenia is a common, chronic disorder characterized by psychosis, cognitive impairments, and deficit symptoms in a subset of patients. Studies of environmental risk factors point to gestation, suggesting that abnormalities in early brain development may play a role in the disorder.¹ Genetic factors also play a role in the risk of schizophrenia.² There are now several genes that are undergoing intensive study because they appear to be susceptibility genes for schizophrenia as well as some of the aforementioned diseases. Disrupted in schizophrenia 1 (DISC1) is one such gene,^3–6 and many aspects of its neurobiology are consistent with a role for DISC1 in schizophrenia.⁷

Genetic Linkage Studies

In addition to increased risk for developing schizophrenia in relatives of those with the disease, numerous studies have found genetic mutations linked to the disease. For example, a (1/11) (q42.1; q14.3) balanced chromosomal translocation was found in a Scottish family.⁸ In affected subjects, a segment of chromosome 1 was located on chromosome 11 and vice versa. This translocation and subsequent dysregulation are what are associated with schizophrenia. Two genes straddle the breakpoint on chromosome 1, one transcript with an open reading frame, DISC1, is expressed as protein; the other transcript, DISC2, is antisense to DISC1 and appears not to be expressed as a protein product.⁶ When a psychiatric evaluation of family members was undertaken, this chromosomal abnormality was associated with an increased risk of psychiatric disorders. The strength of the association between the chromosomal translocation and psychiatric illness was greatest for a broad phenotype that included schizophrenia, major depression, and bipolar disorder.^6,9–11 This association has now been extended to the general Scottish population and beyond.^12,13 For example, a frame shift mutation in DISC1 has been reported in American probands with schizophrenia.¹⁴ The most significant finding in a linkage analysis of schizophrenia in a Finnish population was an intragenic marker in the DISC1 gene,¹⁵ a finding confirmed with haplotype transmission analysis.¹⁶ In a Taiwanese sample, 2 single nucleotide polymorphisms (SNPs) between introns 4 and 5 of the DISC1 gene were identified in single locus and haplotype association analyses.¹⁷

Moreover, associations have been found between mutant DISC1 and specific symptoms in schizophrenia and bipolar disorder. An exonic SNP in DISC1 is associated with normal cognitive changes in the aging process.¹⁸ Using SNPs, Liu et al¹⁷ found an association between abnormal DISC1 and schizophrenic patients who had deficits in sustained attention. The mutant DISC1 genotype also appears to be related to some of the neurocognitive deficits present in schizophrenia, such as memory problems.^19,20 Using human lymphoblasts, certain haplotypes of abnormal DISC1 mRNA are associated with manic symptoms in bipolar subjects.⁹ Although mutant DISC1 has not been identified as a gene of risk in all populations tested thus far, the overwhelming evidence points to a role for DISC1, and/or its associated proteins, in these illnesses.

Location and Function in Schizophrenic Brain

Most of DISC1 studies to date have not examined postmortem brains from schizophrenia subjects. However, evidence from experimental animals and normal human has shown that DISC1 is present in critical brain regions known to be abnormal in schizophrenia,²¹ including human cerebral cortex²² and hippocampus.²³ The subcellular distribution of one of the DISC isoforms is altered in orbitofrontal cortex in schizophrenia.²⁴ A particular allelic variation in DISC1 is associated with altered structure and function of the hippocampus.²⁵ The expression of NUDEL, LIS1, and FEZ1, binding partners of DISC1, are reduced in hippocampus and prefrontal cortex of subjects with schizophrenia; interestingly, DISC1 mRNA was normal in this study.²⁶ Schizophrenic patients with aberrant expression of the DISC1 gene have reduced frontal cortical gray matter volume.²⁰

DISC1 in Animal Models

Animal models of human brain disorders are crucially important in trying to elucidate the pathophysiology of disease. Unfortunately, there are no animal models that mimic hallucinations, delusions, and thought disorder. There are, however, many partial models that provide valuable information on specific symptoms, the role of neurodevelopment, neuropathology in a given brain region, the side effects or therapeutic mechanisms of antipsychotic medications, and the relationships between some of these factors. Importantly, cloned cDNA of DISC1 has very similar sequences in nucleotides and amino acids between human and monkey.²⁷ Although the sequence conservation is poor between humans and rodents, the regional expression profiles are similar.²⁷ Genetically manipulated mice are useful to study the role of schizophrenia susceptibility genes, such as DISC1. These studies can be very informative about the role of DISC1 in normal development and behavior and whether abnormalities in the gene cause similar neuropathology and functional deficits to that present in subjects with schizophrenia.^7,28 For instance, impaired working memory is produced in C57BL/6J mice when the mutant DISC1 protein found specifically in the 129S6/SvEv strain of mouse is transferred to the C57BL/6J strain.²⁹ mRNA expression in the brains of rodents treated with antipsychotic drugs indicates that some antipsychotics increase DISC1 expression in prefrontal cortex and hippocampus.³⁰ In cell culture, DISC1 overexpression in COS-7 cells causes mitochondrial reorganization, suggesting a role for DISC1 in mitochondrial fission and/or fusion.³¹

DISC1 in the Developing Brain

The results of multiple investigations indicate a role for DISC1 in brain development. In the mouse, DISC1 is expressed from embryonic day 10 through adult life.^32,33 In mouse brain, neocortex and limbic regions, the bed nucleus of the stria terminalis, and some thalamic nuclei express DISC1 during development. Observations during development suggest that DISC1 is involved in neurite outgrowth^34,35 and neuronal migration.^36,37 NUDEL, a protein essential for cortical development, neuronal migration, and axon growth, fails to bind to the mutant DISC1. This results in inhibition of neurite outgrowth in vitro and abnormal cortical development in vivo.^34,37,38 Disruption of normal development may contribute to the reduced neuropil volume found in postmortem cortex in schizophrenia²¹ and in reduced frontal cortical gray matter volume in schizophrenic patients with the mutant DISC1 gene.²⁰ The amount of DISC1 peaks in the mouse brain during the time of embryonic neurogenesis and again during puberty,^32,33 two critical time points implicated in the pathophysiology of schizophrenia.¹ DISC1 appears to change location and function between the developing and the mature brain. Other examples of proteins that do this include reelin, growth-associated protein, neural cell adhesion molecule, and brain-derived neurotrophic factor (Roberts et al³⁹ and references therein).

DISC1 in the Adult Brain

The prevalence of DISC1 in the adult brain is substantial, but maybe somewhat less so than during development, at least for the mouse.^3,33 In adult mouse, DISC1 is prominently expressed in the hippocampus, cerebellum, olfactory bulb, and cerebral cortex,^32,35 where it is found in both excitatory and inhibitory neurons.³³ In adult monkeys, DISC1 is highly localized in many brain regions, is particularly robust in the limbic system, and is more extensively distributed than in the mouse.⁴⁰ In monkeys, expression was more prominent in the dentate gyrus and lateral septum than in cerebral cortex, amygdala, hypothalamus, cerebellum, and the interpeduncular and subthalamic nuclei. In humans, DISC1 has been located in multiple neuronal populations in both hippocampus²³ and neocortex.²² In neocortex, DISC1 staining is widespread and includes both pyramidal and nonpyramidal neurons (figure 1). No obvious differences in labeling pattern were seen across the cortical areas, suggesting a similar cellular function for DISC1 in these regions. At the ultrastructural level in the prefrontal cortex,²² ribosomes, rough endoplasmic reticulum, and synaptic structures were frequently, but not always, labeled (figure 2). In contrast, the machinery of protein excretion and mitochondria were not immunoreactive. The presence of DISC1 on the pre- and/or postsynaptic side of asymmetric synapses suggests the involvement of DISC1 in corticocortical and thalamocortical connections because cortical and thalamic connections both form this type of synapse.⁴¹ The presence of DISC1 in symmetric synapses suggests its involvement in inhibitory local circuit connections within the cortex because cortical interneurons form this type of synapse.⁴¹ The electron microscopic localization of DISC1 in the nucleus is consistent with molecular evidence showing that the DISC1 gene contains the nuclear localization signal and leucine-zipper motifs that are frequently found in nuclear proteins.²² Moreover, both Sawamura et al²⁴ and James et al²³ found DISC1 immunoreactivity in nuclear fractions using subcellular fractionation and cell culture, respectively.

Fig. 1.

Light micrograph of DISC1. Human prefrontal cortex immunolabeled for DISC1 (brown) and counterstained with cresyl violet (blue). Note cell body labeling, especially in pyramidal cells (green arrows), and rich neuropil staining. Labeling in proximal dendrites is common (red arrowheads). Scale bar = 50 μm.

Fig. 2.

Electron micrograph of DISC1. Human prefrontal cortex labeling of axon terminals, spines, and postsynaptic densities (PSD). Note that only a subset of spines, PSDs, and axon terminals are immunoreactive. Scale bar = 1 μm.

Results of molecular and ultrastructural studies suggest that DISC1 interacts with a number of proteins, including centrosome and cytoskeletal proteins, proteins that localize receptors to membranes, and signal transduction proteins.^22,34,42,43 DISC1 labeling of some microtubules²² is consistent with other reports showing DISC1 interactions with cytoskeletal elements.⁴⁴ The relationship of mutant DISC1 with microtubules causes abnormal neurite extension in development and could cause problems with proper cellular movement of mitochondria in both development and adult. In adult humans, DISC1 is prevalent throughout the cortical layers in multiple populations of neurons, axon terminals, and postsynaptic targets.²² The location of DISC1 at many synapses suggests that it may play a role in synaptic function in the adult brain.²² In conclusion, many features of the neurobiology of DISC1 make it a highly likely candidate for a role in some of the many neuropsychiatric problems that afflict patients with schizophrenia and, perhaps, other major mental illnesses.^6,45