Schizophrenia Bulletin Advance Access originally published online on November 30, 2006
Schizophrenia Bulletin 2007 33(1):11-15; doi:10.1093/schbul/sbl063
© The Author 2006. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org.
Schizophrenia in Translation: Disrupted in Schizophrenia (DISC1): Integrating Clinical and Basic Findings
Rosalinda C. Roberts1,2
2 Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, PO Box 21247, Baltimore, MD 21228
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Abstract
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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.
Keywords: development / schizophrenia / genetics / postmortem / plasticity
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Introduction
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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
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Genetic Linkage Studies
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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.
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Location and Function in Schizophrenic Brain
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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 cortex
22 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
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DISC1 in Animal Models
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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
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DISC1 in the Developing Brain
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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 schizophrenia
21 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 al
39 and references therein).
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DISC1 in the Adult Brain
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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 hippocampus
23 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 al
24 and James
et al
23 found
DISC1 immunoreactivity in nuclear fractions using
subcellular fractionation and cell culture, respectively.
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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.
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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.
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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 microtubules
22 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
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Footnotes |
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1 To whom correspondence should be addressed; tel: 410-402-7608, fax: 410-402-6066, e-mail: rroberts{at}mprc.umaryland.edu.
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Abstract
Introduction