The GABAergic system in schizophrenia

Abstract

A defect in neurotransmission involving γ-amino butyric acid (GABA) in schizophrenia was first proposed in the early 1970s. Since that time, a considerable effort has been made to find such a defect in components of the GABAergic system. After a brief introduction focusing on historical perspectives, this paper reviews postmortem and other biological studies examining the following components of the GABAergic system in schizophrenic subjects : the GABA biosynthetic enzyme, glutamate decarboxylase ; free GABA ; the GABA transporter ; the GABA A , GABA B and benzodiazepine receptors ; and the catabolic enzyme GABA transaminase. Additionally, post-mortem studies using morphology or calcium-binding protein to identify GABAergic neurons are also reviewed. Substantial evidence argues for a defect in the GABAergic system of the frontal cortex in schizophrenia which is limited to the parvalbumin-class of GABAergic interneurons.

Neuropharmacological and Neurobiological Relevance of In vivo 1H-MRS of GABA and Glutamate for Preclinical Drug Discovery in Mental Disorders

“…It is of further note that overall variability of GABA, glutamate, and glutamine measurements were on par with CRLBs, thus providing further support for well-balanced contributions of biological and technical variability. Taken together, spectral quality and reliability achieved here in routine investigations translate to propitious sensitivity limits for pharmacoMRS of GABA, glutamate, and glutamine that lie well within the range of tissular alterations reported for psychiatric disorders and respective pharmacological treatments in humans (Blum and Mann, 2002;Hashimoto et al, 2007).…”

GABAergic dysfunction in mood disorders

“…First, reported abnormalities may not be specific to mood disorders, as GABAergic alterations have also been suggested in the pathophysiology of schizophrenia 283 and panic disorder. 284,285 Also, evidence that GABAergic modulation results in antidepressant effects is still missing, although robust evidence of efficacy of GABAergic medications has been shown in bipolar disorder patients.…”

GAD1 (2q31.1), which encodes glutamic acid decarboxylase (GAD67), is associated with childhood-onset schizophrenia and cortical gray matter volume loss

“…Increased GABA A receptor binding has been reported in layers I and II of the cingulate cortex, and reduced GABA uptake and defective GABA release reported, implying that GABA transmission may be affected in schizophrenics. 2,3 Glutamic acid decarboxylase (GAD) is the key enzyme in the synthesis of GABA in inhibitory interneurons. GAD exists as two isoforms (GAD 67 and GAD 65 ) with molecular masses of 67 and 65 kDa, which are encoded by different independently regulated genes on chromosomes 2 (GAD1) and 10 (GAD2), respectively.…”