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 γ-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 α4 and δ 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 α4 and δ subunits in prefrontal cortex from 23 matched pairs of schizophrenia and comparison subjects. Results: 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, the authors 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. 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 GABA _A receptor α1 subunit, and neither δ nor α4 mRNA levels were altered in rodent models of altered excitatory neurotransmission. Conclusions: Since GABA _A receptor α1 subunits also have lower mRNA levels in schizophrenia, show increased expression with age in monkey prefrontal cortex, and can coassemble with δ subunits to form functional GABA _A receptors, lower δ mRNA levels in schizophrenia might reflect a reduced number of α ₁ β _x δ GABA _A receptors that could contribute to deficient tonic inhibition and prefrontal cortical dysfunction in schizophrenia.