Altered excitatory and inhibitory ionotropic receptor subunit expression in the cortical visuospatial working memory network in schizophrenia.

Abstract

Dysfunction of the cortical dorsal visual stream and visuospatial working memory (vsWM) network in individuals with schizophrenia (SZ) likely reflects alterations in both excitatory and inhibitory neurotransmission within nodes responsible for information transfer across the network, including primary visual (V1), visual association (V2), posterior parietal (PPC), and dorsolateral prefrontal (DLPFC) cortices. However, the expression patterns of ionotropic glutamatergic and GABAergic receptor subunits across these regions, and alterations of these patterns in SZ, have not been investigated. We quantified transcript levels of key subunits for excitatory N-methyl-D-aspartate receptors (NMDARs), excitatory alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs), and inhibitory GABAA receptors (GABAARs) in postmortem total gray matter from V1, V2, PPC, and DLPFC of unaffected comparison (UC) and matched SZ subjects. In UC subjects, levels of most AMPAR and NMDAR mRNAs exhibited opposite rostral-to-caudal gradients, with AMPAR GRIA1 and GRIA2 mRNA levels highest in DLPFC and NMDAR GRIN1 and GRIN2A mRNA levels highest in V1. GABRA5 and GABRA1 mRNA levels were highest in DLPFC and V1, respectively. In SZ, most transcript levels were lower relative to UC subjects, with these differences largest in V1, intermediate in V2 and PPC, and smallest in DLPFC. In UC subjects, these distinct patterns of receptor transcript levels across the cortical vsWM network suggest that the balance between excitation and inhibition is achieved in a region-specific manner. In SZ subjects, the large deficits in excitatory and inhibitory receptor transcript levels in caudal sensory regions suggest that abnormalities early in the vsWM pathway might contribute to altered information processing in rostral higher-order regions.