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 gamma-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 alpha 4 and delta 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 alpha 4 and delta subunits in prefrontal cortex from 23 matched pairs of schizophrenia and comparison subjects. Results: Levels of delta mRNA were significantly lower in schizophrenia subjects regardless of medication use, whereas alpha 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 alpha 4 and delta subunit expression in schizophrenia, the authors used similar methods to quantify alpha 4 and delta mRNA levels in multiple animal models. During postnatal development of monkey prefrontal cortex, levels of alpha 4 mRNA decreased, whereas delta mRNA levels increased. In addition, delta mRNA levels, but not alpha 4 mRNA levels, were lower in the medial frontal cortex of mice with a genetic deletion of the GABA(A) receptor alpha 1 subunit, and neither delta nor alpha 4 mRNA levels were altered in rodent models of altered excitatory neurotransmission. Conclusions: Since GABA(A) receptor alpha 1 subunits also have lower mRNA levels in schizophrenia, show increased expression with age in monkey prefrontal cortex, and can coassemble with delta subunits to form functional GABA(A) receptors, lower delta mRNA levels in schizophrenia might reflect a reduced number of alpha(1)beta(x)delta GABA(A) receptors that could contribute to deficient tonic inhibition and prefrontal cortical dysfunction in schizophrenia.