GAD67 and GAD65 mRNA and protein expression in cerebrocortical regions of elderly patients with schizophrenia

Abstract

Gamma-Aminobutyric acid (GABA), the principal inhibitory neurotransmitter of CNS, has been consistently implicated in the pathophysiology of schizophrenia. GABA is synthesized from glutamate by the enzyme glutamic acid decarboxylase (GAD). Two isoforms of GAD have been identified and have been named GAD65 and GAD67 based on their apparent molecular weights. In this study, GAD65 and GAD67 mRNA and protein levels were measured by using real-time RT-PCR and immunoblotting, respectively, in post-mortem brain tissue from the dorsolateral prefrontal cortex (DLPFC) and the occipital cortex of the elderly persons with schizophrenia and matched normal controls. In addition, the mRNA expression of GAT-1, one of the principal transporters of GABA, was also studied in the same subjects. Expression of GAD65 and GAD67 mRNA in the DLPFC and in the occipital cortex was significantly elevated in patients with schizophrenia, whereas the expression of the corresponding proteins and GAT-1 mRNA was unchanged. Although the levels of GAD65 and GAD67 messages were increased in schizophrenia subjects, the proportion of the two GAD isoforms remained constant in controls and schizophrenics. In the human DLPFC, GAD65 mRNA was found to be expressed significantly less than the message for GAD67, approximately 16% of that observed for GAD67. On the contrary, the abundance of GAD65 protein in the DLPFC was about 350% of that observed for GAD67. The results suggest a substantial dysregulation of GAD mRNA expression in schizophrenia and, taken together with the results of protein expression studies, raise the possibility that both cortical and subcortical GABA function may be compromised in the disease.

Glial–Neuronal Interactions are Impaired in the Schizophrenia Model of Repeated MK801 Exposure

“…The amount of GABA and [1,2-13 C]GABA from [1,2-13 C]acetate remained unchanged, whereas, [2-13 C]GABA was decreased in the CRFC in the present study. Thus, GABA turnover from [1-13 C]glucose was affected, which corroborates recent reports of impaired activity of glutamic acid decarboxylase (GAD) in schizophrenic patients (Guidotti et al, 2000;Volk et al, 2000;Dracheva et al, 2004). In this context, it is noteworthy that a decrease in GAD 67 has been suggested as a link between the glutamatergic and dopaminergic theories of psychosis (Hossein Fatemi et al, 2005).…”

Transcript-Specific Associations of SLC12A5 (KCC2) in Human Prefrontal Cortex with Development, Schizophrenia, and Affective Disorders

“…Decreased GAD67 is one of the most highly replicated postmortem findings in patients with schizophrenia (Akbarian et al, 1995;Guidotti et al, 2000;Dracheva et al, 2004;Fatemi et al, 2005). Although levels of full-length KCC2 mRNA expression are not significantly altered in the DLPFC in schizophrenia, the levels of the truncated transcript of KCC2 AK098371 are reduced.…”

Brain-Derived Neurotropic Factor/TrkB Signaling in the Pathogenesis and Novel Pharmacotherapy of Schizophrenia

“…Moreover, decreased GAD65 as well as GAD67 mRNA expression in prefrontal and other neocortical association areas of schizophrenics has been reported in different studies that used postmortem tissue from different brain banks [70] . Studies have also reported increased GAD67 mRNA and protein levels in prefrontal and primary sensory (visual) cortices of elderly schizophrenia subjects [71] . Since a reduction of GABAergic neurons results in a loss of the key modulatory inhibition of the pyramidal and interneuron processes, which may mediate the central executive function of working memory in schizophrenia subjects, several studies have looked at the effect of GABAergic agents in the treatment of schizophrenia [72][73] .…”