GABA_A Receptor Subunit Gene Expression in Human Prefrontal Cortex: Comparison of Schizophrenics and Controls

Abstract

The prefrontal cortex of schizophrenics is hypoactive and displays changes related to inhibitory, GABAergic neurons, and GABAergic synapses. These changes include decreased levels of glutamic acid decarboxylase (GAD), the enzyme for GABA synthesis, upregulation of muscimol binding, and downregulation of benzodiazepine binding to GABAA receptors. Studies in the visual cortex of nonhuman primates have demonstrated that gene expression for GAD and for several GABAA receptor subunit polypeptides is under control of neuronal activity, raising the possibility that similar mechanisms in the hypoactive prefrontal cortex of schizophrenics may explain the abnormalities in GAD and in GABAA receptor regulation. In the present study, which is the first of its type on human cerebral cortex, levels of mRNAs for six GABAA receptor subunits (alpha 1, alpha 2, alpha 5, beta 1, beta 2, gamma 2) and their laminar expression patterns were analyzed in the prefrontal cortex of schizophrenics and matched controls, using in situ hybridization histochemistry and densitometry. Three types of laminar expression pattern were observed: mRNAs for the alpha 1, beta 2, and gamma 2 subunits, which are the predominant receptor subunits expressed in the mature cortex, were expressed at comparatively high levels by cells of all six cortical layers, but most intensely by cells in lower layer III and layer IV. mRNAs for the alpha 2, alpha 5, and beta 1 subunits were expressed at lower levels; alpha 2 and beta 1 were expressed predominantly by cells in layers II, III, and IV; alpha 5 was expressed predominantly in layers IV, V, and VI. There were no significant changes in overall mRNA levels for any of the receptor subunits in the prefrontal cortex of schizophrenics, and the laminar expression pattern of all six receptor subunit mRNAs did not differ between schizophrenics and controls. Because gene expression for GABAA receptor subunits is not consistently altered in the prefrontal cortex of schizophrenics, the previously reported upregulation of muscimol binding sites and downregulation of benzodiazepine binding sites in the prefrontal and adjacent cingulate cortex of schizophrenics are possibly due to posttranscriptional modifications of mRNAs and their translated polypeptides.

Alterations in GABA-related transcriptome in the dorsolateral prefrontal cortex of subjects with schizophrenia

“…Consistent with this interpretation, another study using 12 pairs of age-, sex-and PMI-matched subjects reported a trend decrease in a1 mRNA levels in schizophrenia. 70 However, future studies of independent cohorts are needed to resolve the differences across studies. Previous studies also reported increased muscimol binding in the DLPFC of schizophrenia subjects that was most prominent in pyramidal neuron cell bodies.…”

Dopamine D1 and D4 Receptor Subtypes Differentially Modulate Recurrent Excitatory Synapses in Prefrontal Cortical Pyramidal Neurons

“…D4 receptor proteins present in high levels in cortical layer II/III or V/VI are associated with both calbindin-and parvalbumin-containing GABA interneurons (Mezljak et al, 1996;Le Moine and Gaspar, 1998;Wedzony et al, 2000). Alterations in GABA transmission in these subclasses of GABAergic neurons have been reported in the PFC of schizophrenia brains examined post mortem (Bird et al, 1977;Akbarian et al, 1995;Lewis, 2000) and in a rat model of amphetamine sensitization (Mohila and Onn, 2005). Although D4 antagonists have not yet been reported to have antipsychotic efficacy (Lahti et al, 1998), both D4 receptor anatgonists, PNU-101387 and L-745870, were reported to prevent or improve cognitive deficits in monkeys (Arnsten et al, 2000) and in rats .…”

Genetic investigation of chromosome 5q GABAA receptor subunit genes in schizophrenia

“…42 The 5q GABA genes are plausible candidates for the schizophrenia risk gene in the 5q locus based on a converging body of literature implicating GABA system dysfunction in schizophrenia pathophysiology. [43][44][45][46][47][48][49] In schizophrenia patient brain samples, markers of GABAergic neurons are reduced in expression and postsynaptic receptor complexes are increased in number. 47,50,51 Furthermore, there is evidence that neuregulin 1 (NRG1) and dysbindin (DTNBP1), two schizophrenia candidate risk genes, 33,[52][53][54][55][56][57][58][59][60][61][62][63][64][65] interact with the GABA A receptor.…”