Lamina-Specific Alterations in Cortical GABA sub(A) Receptor Subunit Expression in Schizophrenia

Dysfunction of the dorsolateral prefrontal cortex (DLPFC) in schizophrenia is associated with lamina-specific alterations in particular subpopulations of interneurons. In pyramidal cells, postsynaptic gamma -aminobutyric acid (GABA sub(A)) receptors containing different alpha subunits are inserted preferentially in distinct subcellular locations targeted by inputs from specific interneuron subpopulations. We used in situ hybridization to quantify the laminar expression of alpha 1, alpha 2, alpha 3, and alpha 5 subunit, and of beta 1-3 subunit, mRNAs in the DLFPC of schizophrenia, and matched normal comparison subjects. In subjects with schizophrenia, mean GABA sub(A) alpha 1 mRNA expression was 17% lower in layers 3 and 4, alpha 2 expression was 14% higher in layer 2, alpha 5 expression was 15% lower in layer 4, and alpha 3 expression did not differ relative to comparison subjects. The mRNA expression of beta 2, which preferentially assembles with alpha 1 subunits, was also 20% lower in layers 3 and 4, whereas beta 1 and beta 3 mRNA levels were not altered in schizophrenia. These expression differences were not attributable to medication effects or other potential confounds. These findings suggest that GABA neurotransmission in the DLPFC is altered at the postsynaptic level in a receptor subunit- and layer-specific manner in subjects with schizophrenia and support the hypothesis that GABA neurotransmission in this illness is predominantly impaired in certain cortical microcircuits.