Alterations in cortical interneurons and cognitive function in schizophrenia

Abstract

Certain clinical features of schizophrenia, such as working memory disturbances, appear to emerge from altered gamma oscillatory activity in the prefrontal cortex (PFC). Given the essential role of GABA neurotransmission in both working memory and gamma oscillations, understanding the cellular substrate for their disturbances in schizophrenia requires evidence from in vivo neuroimaging studies, which provide a means to link markers of GABA neurotransmission to gamma oscillations and working memory, and from postmortem studies, which provide insight into GABA neurotransmission at molecular and cellular levels of resolution. Here, we review findings from both types of studies which converge on the notions that 1) inhibitory GABA signaling in the PFC, especially between parvalbumin positive GABAergic basket cells and excitatory pyramidal cells, is required for gamma oscillatory activity and working memory function; and 2) disturbances in this signaling contribute to altered gamma oscillations and working memory in schizophrenia. Because the PFC is only one node in a distributed cortical network that mediates working memory, we also review evidence of GABA abnormalities in other cortical regions in schizophrenia.

Keywords: Cognition; GABA; Interneurons; Neuroimaging; Schizophrenia; Working memory.

Fig. 1.

Schematic summary of alterations in cortical GABA neurons in the PFC of individuals with schizophrenia as revealed in studies of postmortem human brain tissue. Arrows next to the presumptive location of the marker of inhibitory interneurons indicate increased, decreased, or unchanged levels of mRNA transcript or protein. Parvalbumin basket cells (PVBCs)-pyramidal cell microcircuits appear to be responsible for gamma oscillations, and alterations indicated here could represent the neural substrate of impaired gamma oscillatory activity seen in patients with schizophrenia. Furthermore, regulation of the activity of either of these components by other classes of interneurons, such as parvalbumin chandelier cells (ChC), somatostatin cells (SST), cholecysto-kinin basket cells (CCKb), or calretinin cells (CR) could alter the activity of the PVBC-pyramidal cell microcircuit responsible for this oscillatory activity and working memory.

Fig. 2.

Schematic summaries of four alternative hypotheses for the upstream factors that may mediate the deficit in GAD67 and PV selectively in PVBCs in the PFC of subjects with schizophrenia. Lighter shading of synaptic boutons indicates weaker pre-synaptic inputs. A.) Downregulation of neuronal pentraxin (NARP) at pyramidal cell inputs could lead to fewer AMPA receptors on PVBCs, and lower activity-dependent transcription of GAD67 and PV in schizophrenia. B.) ErbB4 splicing variants in PV cells regulate the density of excitatory inputs onto these cells, such that higher expression of the minor variants (CYT1 and JM-a) compared to the major variants (CYT2 and JM-b) results in fewer excitatory inputs onto PV cells in schizophrenia. Indeed, PV cells in the PFC of individuals with schizophrenia have higher expression of the minor splicing variants which may lead to the fewer excitatory inputs to PVBCs, contributing to reduced expression of the activity dependent genes, GAD67 and PV. C.) A decrease in the constituents of the perineuronal nets surrounding PVBCs, by reducing protection against oxidative stress, may lead to a downregulation of transcripts that encode for GAD67 and PV protein. D.) An intrinsic deficit in actin regulation, leading to lower density of dendritic spines and fewer excitatory inputs to pyramidal cells, results in lower excitatory drive to PVBCs and downregulation of GAD67 and PV. The resulting downregulation of feedback inhibition to hypoactive pyramidal cells may help maintain excitatory-inhibitory balance in this cortical microcircuit, but at the cost of impairing the generation of gamma oscillations (Gonzalez-Burgos et al., 2015).

Fig. 3.

Schematic summary of the results of a study that systemically investigated GABA markers in layer 3 across four cortical regions critical for vi-suospatial working memory. Measures of a composite GABA score were obtained by summation of normalized z-scores for the expression ratio of transcripts common to all GABA neurons in each brain region for both diagnostic groups, providing each equal weight to each transcript measured. The colors indicate each brain region studied, and the data points reflect these summated scores of GABA markers in each region by diagnosis. In healthy comparison subjects (solid line), GABA markers have lowest expression in layer 3 of the dorsolateral PFC (DLPFC), and progressively increase in the posterior parietal cortex (PPC), the visual association cortex (V2), achieving the highest expression in the primary visual cortex (V1). In individuals with schizophrenia (dashed line), this rostral to caudal gradient is enhanced, such that GABA markers are markedly downregulated in the DLPFC and upregulated in V1. Alterations in the set point of inhibition may contribute to disrupted visuos-patial working memory in subjects with schizophrenia. Data in figure adapted from (Hoftman et al., 2018).