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Altered Markers of Tonic Inhibition in the Dorsolateral Prefrontal Cortex of Subjects With Schizophrenia

OBJECTIVE: Cognitive impairments in schizophrenia are associated with lower expression of markers of -aminobutyric acid (GABA) synthesis in the prefrontal cortex. The effects of GABA are mediated by GABA_A receptors that mediate either phasic or tonic inhibition. The authors assessed the expression of GABA_A receptor 4 and subunits, which coassemble to form receptors mediating tonic inhibition, in schizophrenia. METHOD: The authors used in situ hybridization to quantify expression patterns of GABA_A receptor 4 and subunits in prefrontal cortex from 23 matched pairs of schizophrenia and comparison subjects. RESULTS: Levels of mRNA were significantly lower in schizophrenia subjects regardless of medication use, whereas 4 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 4 and subunit expression in schizophrenia, the authors used similar methods to quantify 4 and mRNA levels in multiple animal models. During postnatal development of monkey prefrontal cortex, levels of 4 mRNA decreased, whereas mRNA levels increased. In addition, mRNA levels, but not 4 mRNA levels, were lower in the medial frontal cortex of mice with a genetic deletion of the GABA_A receptor 1 subunit, and neither nor 4 mRNA levels were altered in rodent models of altered excitatory neurotransmission. CONCLUSIONS: Since GABA_A receptor 1 subunits also have lower mRNA levels in schizophrenia, show increased expression with age in monkey prefrontal cortex, and can coassemble with subunits to form functional GABA_A receptors, lower mRNA levels in schizophrenia might reflect a reduced number of ₁β_x GABA_A receptors that could contribute to deficient tonic inhibition and prefrontal cortical dysfunction in schizophrenia.

This article has been cited by other articles:

				What Interferes with Inhibitory Functions in the Prefrontal Cortex in Schizophrenia? Journal Watch Psychiatry, May 4, 2009; 2009(504): 4 - 4. [Full Text]

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