Markers of glutamate and GABA neurotransmission in the prefrontal cortex of schizophrenia subjects: Disease effects differ across anatomical levels of resolution.

Cognitive dysfunction in individuals with schizophrenia is thought to reflect, at least in part, altered levels of excitatory and inhibitory neurotransmission in the dorsolateral prefrontal cortex (DLPFC). Studies of the postmortem human brain allow for interrogation of the disease-related alterations in markers of excitatory and inhibitory neurotransmission at different levels of anatomical resolution. Here, we re-analyzed six published datasets from postmortem studies of schizophrenia to assess molecular markers of glutamate and GABA neurotransmission in the DLPFC at three levels of anatomical resolution: 1) total cortical gray matter, 2) gray matter restricted to layer 3, and 3) a layer 3 local circuit composed of excitatory pyramidal cells and inhibitory, parvalbumin-containing, GABA neurons. We formulated composite measures of glutamate and GABA neurotransmission from z-scores of key transcripts that regulate these functions. Relative to unaffected comparison subjects, the composite glutamate measure was higher in schizophrenia subjects in total gray matter homogenates but lower in samples restricted to layer 3 or the layer 3 local circuit. The composite index of GABA neurotransmission did not differ between subject groups in total gray matter homogenates but was lower in schizophrenia subjects in layer 3 and lower still in the local layer 3 circuit. These findings suggest that the balance of excitation and inhibition in the DLPFC of schizophrenia subjects differs depending on the level of anatomical resolution studied, highlighting the importance of layer- and cell type-specific studies to understand disease-related alterations in cortical circuitry.