GAD1 Gene Expression in Blood of Patients with First-Episode Psychosis.

Jie Yin Yee,Tih-Shih Lee,Milawaty Nurjono,Jimmy Lee,Stephanie Ruth Teo,Xiang Yang Zhang

doi:10.1371/journal.pone.0170805

Abstract

γ-Aminobutyric acid (GABA), the primary inhibitory neurotransmitter, has often been studied in relation to its role in the pathophysiology of schizophrenia. GABA is synthesized from glutamate by glutamic acid decarboxylase (GAD), derived from two genes, GAD1 and GAD2. GAD1 is expressed as both GAD67 and GAD25 mRNA transcripts with the former reported to have a lower expression level in schizophrenia compared to healthy controls and latter was reported to be predominantly expressed fetally, suggesting a role in developmental process. In this study, GAD67 and GAD25 mRNA levels were measured by quantitative PCR (qPCR) in peripheral blood of subjects with first-episode psychosis (FEP) and from healthy controls. We observed low GAD25 and GAD67 gene expression levels in human peripheral blood. There was no difference in GAD25 and GAD67 gene expression level, and GAD25/GAD67 ratio between patients with FEP and healthy controls. PANSS negative symptoms were associated with levels of GAD25 mRNA transcripts in patients with FEP. While the current study provides information on GAD25 and GAD67 mRNA transcript levels in whole blood of FEP patients, further correlation and validation work between brain regions, cerebrospinal fluid and peripheral blood expression profiling are required to provide a better understanding of GAD25 and GAD67.

Highlights

Alterations in GABAergic inhibitory neurotransmission have been reported in schizophrenia [1]
While studies in the literature on GAD1 in psychosis were conducted primarily on postmortem brain samples, the current study is the first to examine GAD1 expression levels in human blood using quantitative PCR (qPCR). We found that both transcripts, GAD25 and GAD67, were lowly expressed in human peripheral blood
There had been varying findings from published reports; while majority observed a reduction in GAD67 expression levels in patients with schizophrenia and mood disorders, two reported that the reduced GAD67 levels were due to subset of GABA neurons and two other studies noted an increase in mRNA level in elderly with schizophrenia [10,11,12,13,14,15,16,17]

Summary

Introduction

Alterations in GABAergic inhibitory neurotransmission have been reported in schizophrenia [1]. GAD1 is the gene which encodes for a 67kDa isoform of glutamic acid decarboxylase, a key enzyme involved in GABA synthesis, and has been intensively studied [1]. GAD67 was found to be localized in several brain regions, in particular, the prefrontal cortex and hippocampus; its expression gradually increased from 14 weeks of gestational age until approximately 10 years of age and plateauing throughout the rest of lifespan [2,3]. Changes in molecular and cellular mechanisms affecting GAD67 were found to interfere with neuronal activity, connectivity formation during development, glutamatergic and dopaminergic neurotransmission and neurotrophin or glycoprotein signaling [1]. Studies comparing GABA levels in subjects in schizophrenia suggested.

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