Elsevier

Brain Research Reviews

Volume 52, Issue 2, September 2006, Pages 293-304
Brain Research Reviews

Review
Molecular and cellular mechanisms of altered GAD1/GAD67 expression in schizophrenia and related disorders

https://doi.org/10.1016/j.brainresrev.2006.04.001Get rights and content

Abstract

The 67 and 65 kDa isoforms of glutamic acid decarboxylase, the key enzymes for GABA biosynthesis, are expressed at altered levels in postmortem brain of subjects diagnosed with schizophrenia and related disorders, including autism and bipolar illness. The predominant finding is a decrease in GAD67 mRNA levels, affecting multiple brain regions, including prefrontal and temporal cortex. Postmortem studies, in conjunction with animal models, identified several mechanisms that contribute to the dysregulation of GAD67 in cerebral cortex. These include disordered connectivity formation during development, abnormal expression of Reelin and neural cell adhesion molecule (NCAM) glycoproteins, defects in neurotrophin signaling and alterations in dopaminergic and glutamatergic neurotransmission. These mechanisms are likely to operate in conjunction with genetic risk factors for psychosis, including sequence polymorphisms residing in the promoter of GAD1 (2q31), the gene encoding GAD67. We propose an integrative model, with multiple molecular and cellular mechanisms contributing to transcriptional dysregulation of GAD67 and cortical dysfunction in psychosis.

Introduction

Dysfunction of cerebral cortex and hippocampus in schizophrenia and related disorders is thought to include alterations in GABAergic, inhibitory neurotransmission (Guidotti et al., 2005, Lewis et al., 2005). The underlying cellular mechanisms include subtle changes in interneuron connectivity (Benes and Berretta, 2001) and a distinct set of molecular and genetic alterations (Harrison and Weinberger, 2005). Among the genes involved in the pathophysiology of cortical dysfunction in schizophrenia is GAD1 (Rapoport et al., 2005), which encodes the 67 kDa isoform of glutamic acid decarboxylase, the key enzyme for GABA synthesis (Bu et al., 1992). Genetic studies linked GAD1 to abnormal neurodevelopment and early (childhood)-onset schizophrenia (Addington et al., 2005, Lundorf et al., 2005) and bipolar disorder (Lundorf et al., 2005). Furthermore, subjects diagnosed with psychosis frequently show dysregulated GAD67 and GAD65 expression in cerebral cortex and other brain regions (Akbarian et al., 1995, Blatt, 2005, Dracheva et al., 2004, Fatemi et al., 2002, Fatemi et al., 2005, Guidotti et al., 2000, Heckers et al., 2002, Torrey et al., 2005, Volk et al., 2000, Woo et al., 2004). As discussed further below, the majority of the studies conducted on postmortem brain tissue from clinical cases report alterations in GAD67 mRNA levels. Therefore, insight into the molecular pathways governing GAD67 gene expression could advance current knowledge on the pathogenesis of psychosis. Studies in animals, complemented by postmortem and other clinical studies, identified several molecular and cellular mechanisms that regulate cortical GAD67 expression. These include changes in neuronal activity, disordered connectivity formation during development, alterations in glutamatergic and dopaminergic neurotransmission and defects in neurotrophin or glycoprotein signaling. This review will summarize, for each of these mechanisms, the relevant findings obtained from animal models and clinical studies. We propose an integrative model to explain GAD67 gene expression changes in psychosis. The model includes allelic polymorphisms in the GAD1 promoter sequence as genetic susceptibility factors, which operate in conjunction with a defined set of maladaptive molecular mechanisms contributing to cortical dysfunction in psychosis.

Section snippets

GAD genes and function

Glutamic acid decarboxylase (GAD) in brain catalyzes synthesis of the inhibitory neurotransmitter gamma-amino butyric acid (GABA). The GABAergic neurons of the mammalian nervous system express two homologous forms of GAD, with protein sizes of 67 and 65 kDa, each encoded by a different gene (Bu et al., 1992, Erlander and Tobin, 1991). It is estimated that GAD67 accounts for 56–85% of the GABA synthesis flux in rat cerebral cortex at baseline (Mason et al., 2001), and up to 80–90% of overall

Altered GAD67 expression in psychosis—functional implications

The initial study on GAD67mRNA expression in prefrontal cortex (PFC) of schizophrenics (Akbarian et al., 1995) was based on a two-fold rationale: First, experiments on visual cortex of cats and non-human primates revealed that GAD67mRNA is heavily regulated by neuronal activity (Benson et al., 1989, Benson et al., 1991). Second, schizophrenia is frequently accompanied by dysfunction and hypoactivity of prefrontal and other cortical areas (Goff and Evins, 1998, Wolkin et al., 1992). Therefore,

Altered GAD65 expression in psychosis

As discussed above, a substantial number of postmortem studies reported significant changes in GAD67 expression in brain of subjects diagnosed with psychosis. A number of studies measured both GAD67 and GAD65 mRNA or protein levels. A comprehensive study by Guidotti et al. (2000) found a deficit in GAD67, but not GAD65 mRNA and protein in prefrontal and cerebellar cortices of schizophrenia and bipolar disorder subjects. In other studies, however, altered levels of GAD67 in cerebral cortex,

Activity-dependent regulation of GAD67 transcription

In visual cortex of non-human primates, a decrease in sensory input from one eye results in a marked reduction of GABA and GAD in ocular dominance columns associated with the deprived eye (Hendry and Jones, 1986). This GABA/GAD effect is apparent within the first 48 h of monocular deprivation (Hendry and Jones, 1986). Because GAD67 mRNA levels appear unchanged within the first 5 days after monocular deprivation (Benson et al., 1991), posttranscriptional mechanisms are thought to be play a

Neurotrophin signaling pathways upstream of GAD67 transcription

The reduction of NMDA receptor-mediated currents is likely to be only one out of several mechanisms by which decreased neuronal activity results in downregulation of GAD67 in cortex of schizophrenics. For example, it is now increasingly recognized that brain-derived neurotrophic factor (BDNF) and its high affinity, receptor, the receptor tyrosine kinase TrkB, are key regulators of inhibitory interneuron function in cerebral cortex and other brain regions. In the cortex, BDNF is synthesized and

Developmental perturbation of cortical connectivity causes long-term changes in GAD67 expression

Brain injuries during the developmental period eventually induce long-lasting changes in the regulation of BDNF and GAD67. For example, excitotoxin-induced ablation of subplate neurons, which comprise a transient population of cells located underneath the developing cortical plate, results in increased levels of BDNF and GAD67 in the overlying cortex for a period lasting at least 6 weeks postinjury (Lein et al., 1999). This observation is of interest, given that some subjects with schizophrenia

Glycoproteins as regulators of GABA/GAD

The neural cell adhesion molecule (NCAM), a member of the immunoglobulin superfamily of molecules, plays an important role for neuronal process outgrowth, synapse formation and signal transduction (Rougon and Hobert, 2003). Intercellular adhesion is regulated by the extracellular region of NCAM (NCAM-EC), which is comprised of immunoglobulin-like and fibronectin III domains (Panicker et al., 2003). Elevated levels of NCAM-EC were reported for the prefrontal cortex and hippocampus of

Regulation of GAD67 and GAD65 expression by antipsychotic drugs

Presently, it is still unclear if the downregulation of cortical GAD67 expression in the clinical samples (Table 1) and in the animal models mentioned above is of relevance for the molecular pathology of schizophrenia and related disorders. If so, one would expect that commonly used therapeutic interventions result in changes opposite to those caused by the disease. Consequently, treatment with antipsychotic drugs would be expected to induce increased expression of GAD67, and possibly also of

Allelic variants of GAD67 confer genetic risk for childhood-onset schizophrenia and bipolar disorder

The 67 kDa isoform of glutamic acid decarboxylase, GAD67, is encoded by GAD1, a gene that resides on the long arm of chromosome 2 (2q31). The GAD1 gene extends across 45 kb of genomic DNA and includes 18 exons (Bu and Tobin, 1994). Addington et al. (2005) examined a group of 72 subjects diagnosed with childhood-onset schizophrenia, a rare subtype of the disorder defined as the onset of psychotic symptoms by age 12 (Nicolson and Rapoport, 1999). They identified a number of adjacent single

An integrative model and future directions

Little is known about the molecular pathology that underlies cortical dysfunction, including defective GABAergic circuitry, in schizophrenia and related disorders. Evidence from postmortem studies and animal models suggests that the GAD67 deficit could result from (i) disordered connectivity formation during development, (ii) alterations in glycoproteins (N-CAM, Reelin) regulating GABAergic synapses, (iii) disruption of neurotrophin signaling pathways (BDNF/TrkB) and (iv) abnormalities in

Acknowledgment

This work was supported by grants from the National Institutes of Health (MH071476 and MH074318-01) to S.A.

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