Decreased glutamic acid decarboxylase67 mRNA expression in multiple brain areas of patients with schizophrenia and mood disorders
Introduction
Schizophrenia is a disabling psychiatric disorder characterized by social withdrawal, hallucinations, working memory impairments, and attentional deficits (Harrison, 1999, Hirsch and Weinberger, 1995). Due to these diverse symptoms, multiple brain areas have been implicated in the disorder, particularly associative areas of neocortex, such as the dorsolateral prefrontal cortex (DLPFC), orbitofrontal cortex (OFC), anterior cingulate cortex (ACC) and superior temporal gyrus (STG). Structural abnormalities seen in subcortical regions, such as the striatum and thalamus which communicate and integrate signals across cortical domains, may also contribute to the aberrant processing detected in schizophrenia (Harms et al., 2007, Mamah et al., 2007). Convergent evidence from several studies suggest that abnormalities in cortical inhibition, specifically involving inhibitory interneurons containing γ-aminobutyric acid (GABA) (Benes and Berretta, 2001, Benes et al., 1991, Lewis et al., 2005, Wassef et al., 2003) exist in the brains of patients with schizophrenia. Numerous studies have documented abnormalities affecting these cortical GABAergic neurons particularly within the DLPFC (Akbarian et al., 1995, Guidotti et al., 2000, Hashimoto et al., 2008a, Ohnuma et al., 1999, Woo et al., 2008), ACC (Benes et al., 2001, Cotter et al., 2002, Hashimoto et al., 2008b, Woo et al., 2004) and hippocampus (Heckers et al., 2002, Reynolds et al., 1990, Zhang et al., 2002) of subjects with schizophrenia and related disorders.
Regulation of GABA neurotransmission is partly due to its rate-limiting synthesizing enzyme glutamate decarboxylase (GAD), which synthesizes GABA from glutamate (Akbarian and Huang, 2006). GAD exists as 2 separate isoforms, GAD65 and GAD67, encoded by two independent genes located on chromosomes 2 and 10, respectively, which differ in their subcellular distribution and biological properties (Bu et al., 1992, Soghomonian and Martin, 1998). Mice mutant for either GAD isoform demonstrate that each plays a role in specific aspects of GABA neurotransmission. GAD65 is associated with GABA packaging and release due to its localization to axon terminals and synaptic vesicle membranes, whereas GAD67 is associated with GABA synthesis and non-vesicular associated release due to its presence in the cytosol (Kaufman et al., 1991, Soghomonian and Martin, 1998, Tian et al., 1999). Of the two isoforms GAD67 is the more interesting with respect to schizophrenia and other mental illnesses because of its ability to be regulated by environmental stimuli (Benson et al., 1994, Soghomonian and Martin, 1998), its consistent alteration in subjects with mental disorders (Akbarian and Huang, 2006, Akbarian et al., 1995, Dracheva et al., 2004, Fatemi et al., 2005, Guidotti et al., 2000, Hashimoto et al., 2003, Heckers et al., 2002, Knable et al., 2002, Torrey et al., 2005, Volk et al., 2000, Woo et al., 2004), and its genetic link to schizophrenia (Addington et al., 2005, Straub et al., 2007).
In this study, we investigated whether the reductions in GAD67 mRNA previously described in schizophrenia extend beyond the DLPFC, ACC, primary sensory and primary motor cortex to other integrative regions of the telencephalon such as the OFC, STG, thalamus, and striatum. We also inquired as to whether the reductions in GAD67 mRNA were diagnostically specific by measuring GAD67 mRNA levels in patients with bipolar disorder and major depression as well as in those with schizophrenia. An understanding of the regional, laminar and diagnostic specificity of GAD67 deficits in schizophrenia and other psychiatric disorders may be a useful guide when considering future therapeutic strategies aimed at the inhibitory system.
Section snippets
Brain cohort
Frozen, 14 μm thick coronal sections from the OFC, ACC, and STG were obtained from the Stanley Foundation Neuropathology Consortium (SFNC; Fig. 1). The OFC sections were from Brodmann area (BA) 45 of the orbital gyrus, the ACC sections were from BA24 of the cingulate gyrus at the level of the genu of the corpus callosum and the STG sections were from BA22 at the level of the geniculate bodies. Coronal sections of the striatum, at the level of the nucleus accumbens (NA) and containing the head of
Orbitofrontal cortex
All subjects showed robust but punctate GAD67 mRNA expression throughout all layers of the OFC (Fig. 1A). The punctate (or spotted) pattern of GAD67 mRNA label seen at the level of autoradiographic film reflected the fact that many neurons were heavily labeled with GAD67 mRNA, but many neurons did not appear to contain GAD-67 mRNA (Fig. S2). Two dark bands of increased GAD67 mRNA expression, one superficial and one deep, were apparent on the films. Subjects with mental illness showed a 30–50%
Discussion
We show that the reduction in GAD67 mRNA is not specific to schizophrenia but can also be detected in patients with bipolar disorder and major depression. This study shows for the first time that GAD67 mRNA levels are reduced in the OFC in patients with schizophrenia, and are also reduced in patients with bipolar disorder and major depression. These findings support and extend results from previous studies that consistently show a decrease of GAD67 mRNA expression in neocortical areas and in
Disclosure/conflicts of interest
The authors declare that, except for income received from my primary employer, no financial support or compensation has been received from any individual or corporate entity over the past three years for research or professional service and there are no personal financial holdings that could be perceived as constituting a potential conflict of interest.
Contributors
Author Mia Thompson performed the statistical analysis and wrote the manuscript. Authors Cynthia Shannon Weickert and Maree Webster designed the study and contributed to composing the manuscript. Author Eugene Wyatt performed the study, quantified the data and performed the preliminary statistical analysis of the data. In addition, all authors contributed to and have approved the final manuscript.
Role of funding source
Funding for this study was provided by the Stanley Medical Research Institute (SMRI); the SMRI had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.
Acknowledgements
The authors thank Laura Zwolinski for her technical expertise and the staff of the Stanley Medical Research Institute (SMRI) Laboratory of Brain Research for their assistance. The research was funded by SMRI.
References (69)
- et al.
Molecular and cellular mechanisms of altered GAD1/GAD67 expression in schizophrenia and related disorders
Brain Research Reviews
(2006) - et al.
GABAergic interneurons: implications for understanding schizophrenia and bipolar disorder
Neuropsychopharmacology
(2001) - et al.
The density of pyramidal and nonpyramidal neurons in anterior cingulate cortex of schizophrenic and bipolar subjects
Biological Psychiatry
(2001) Are schizophrenic and bipolar disorders related? A review of family and molecular studies
Biological Psychiatry
(2000)- et al.
The density and spatial distribution of GABAergic neurons, labelled using calcium binding proteins, in the anterior cingulate cortex in major depressive disorder, bipolar disorder, and schizophrenia
Biological Psychiatry
(2002) - et al.
Schizophrenia and anteroventral thalamic nucleus: selective decrease of parvalbumin-immunoreactive thalamocortical projection neurons
Psychiatry Research
(1998) - et al.
Facial emotion discrimination: III. Behavioral findings in schizophrenia
Psychiatry Research
(1992) - et al.
The functional neuroanatomy of the human orbitofrontal cortex: evidence from neuroimaging and neuropsychology
Progress in Neurobiology
(2004) - et al.
Anatomic evaluation of the orbitofrontal cortex in major depressive disorder
Biological Psychiatry
(2004) - et al.
Circuit-based framework for understanding neurotransmitter and risk gene interactions in schizophrenia
Trends in Neuroscience
(2008)
Structural analysis of the basal ganglia in schizophrenia
Schizophrenia Research
Molecular characterization of schizophrenia viewed by microarray analysis of gene expression in prefrontal cortex
Neuron
Olfactory identification in elderly schizophrenia and Alzheimer’s disease
Neurobiology of Aging
Measurement of GABAergic parameters in the prefrontal cortex in schizophrenia: focus on GABA content, GABA(A) receptor alpha-1 subunit messenger RNA and human GABA transporter-1 (HGAT-1) messenger RNA expression
Neuroscience
The volume of the mediodorsal thalamic nucleus in treated and untreated schizophrenics
Schizophrenia Research
Functional anatomy of the basal ganglia. I. The cortico-basal ganglia-thalamo-cortical loop
Brain Research Brain Research Review
Morphometric evidence for neuronal and glial prefrontal cell pathology in major depression
Biologicall Psychiatry
Deficit and hemispheric asymmetry of GABA uptake sites in the hippocampus in schizophrenia
Biological Psychiatry
The functions of the orbitofrontal cortex
Brain Cognition
Two isoforms of glutamate decarboxylase: why?
Trends in Pharmacological Science
The basal ganglia: anatomy, physiology, and pharmacology
Psychiatric Clinic of North America
The stanley foundation brain collection and neuropathology consortium
Schizophrenia Research
Neurochemical markers for schizophrenia, bipolar disorder, and major depression in postmortem brains
Biological Psychiatry
Epigenetic mechanisms expressed in basal ganglia GABAergic neurons differentiate schizophrenia from bipolar disorder
Schizophrenia Research
Disease-specific alterations in glutamatergic neurotransmission on inhibitory interneurons in the prefrontal cortex in schizophrenia
Brain Research
Reduced number of mediodorsal and anterior thalamic neurons in schizophrenia
Biological Psychiatry
GAD1 (2q311), which encodes glutamic acid decarboxylase (GAD67), is associated with childhood-onset schizophrenia and cortical gray matter volume loss
Molecular Psychiatry
Gene expression for glutamic acid decarboxylase is reduced without loss of neurons in prefrontal cortex of schizophrenics
Archives of General Psychiatry
Alterations in prodynorphin, proenkephalin, and GAD67 mRNA levels in the aged human putamen: correlation with Parkinson’s disease
Journal of Neuroscience Research
Deficits in small interneurons in prefrontal and cingulate cortices of schizophrenic and schizoaffective patients
Archives of General Psychiatry
Activity-dependent changes in GAD and preprotachykinin mRNAs in visual cortex of adult monkeys
Cerebral Cortex
Two human glutamate decarboxylases, 65-kDa GAD and 67-kDa GAD, are each encoded by a single gene
Proceedings of the National Academy of Sciences of the United States of America
GAD67 and GAD65 mRNA and protein expression in cerebrocortical regions of elderly patients with schizophrenia
Journal of Neuroscience Research
GABAergic dysfunction in schizophrenia and mood disorders as reflected by decreased levels of glutamic acid decarboxylase 65 and 67 kDa and Reelin proteins in cerebellum
Schizophrenia Research
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