Feature Finding Title
Featured Finding Figure

Cognitive impairments in schizophrenia are associated with lower expression of markers of GABA synthesis in the prefrontal cortex. The effects of GABA are mediated by GABAA receptors that mediate either phasic or tonic inhibition. We assessed the expression of GABAA receptor α4 and δ subunits, which co-assemble to form receptors mediating tonic inhibition in prefrontal cortex from 23 matched pairs of schizophrenia and control subjects. Levels of δ mRNA were significantly lower in schizophrenia subjects regardless of medication use, whereas α4 mRNA levels were lower only in subjects with schizophrenia receiving certain medications at the time of death. To understand the nature of this unexpected dissociation between α4 and δ subunit expression in schizophrenia, we used similar methods to quantify α4 and δ mRNA levels in multiple animal models. During postnatal development of monkey prefrontal cortex, levels of α4 mRNA decreased, whereas δ mRNA levels increased (Figure). In addition, δ mRNA levels, but not α4 mRNA levels, were lower in the medial frontal cortex of mice with a genetic deletion of the GABAA receptor α1 subunit, and neither δ nor α4 mRNA levels were altered in rodent models of altered excitatory neurotransmission. Since GABAA receptor α1 subunits also have lower mRNA levels in schizophrenia, show increased expression with age in monkey prefrontal cortex, and can co-assemble with δ subunits to form functional GABAA receptors, lower δ mRNA levels in schizophrenia might reflect a reduced number of α1βxδ GABAA receptors that could contribute to deficient tonic inhibition and prefrontal cortical dysfunction in schizophrenia.

Jaime G. Maldonado-Avilés, Allison A. Curley, Takanori Hashimoto, A. Leslie Morrow, Amy J. Ramsey, Patricio O’Donnell, David W. Volk and David A. Lewis, Altered Markers of Tonic Inhibition in the Dorsolateral Prefrontal Cortex of Subjects with Schizophrenia, Am J Psychiatry 166: 450-459, 2009.

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David A. Lewis, M.D. | Department of Psychiatry | University of Pittsburgh
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