Perisomatic inhibition and cortical circuit dysfunction in schizophrenia

Abstract

Deficits of cognitive control in schizophrenia are associated with altered gamma oscillations in the prefrontal cortex. Paralbumin basket interneurons, which innervate the perisomatic region of pyramidal neurons, appear to play a key role in generating cortical gamma oscillations. In the prefrontal cortex of subjects with schizophrenia, alterations are present in both pre- and post-synaptic markers of the strength of GABA inputs from parvalbumin basket neurons to pyramidal neurons. These alterations may contribute to the neural substrate for impaired gamma oscillations in schizophrenia.

Figure 1

Schematic summary of the three main types of GABA neurons providing perisomatic inputs to pyramidal neurons and the ratio of the two GABA synthesizing enzymes in the axon terminal levels of each cell type. Adapted from [32].

Figure 2

Schematic summary of layer-specific transcript alterations in postsynaptic GABA_A receptor subunits in the DLPFC of subjects with schizophrenia and their hypothesized relationship to different classes of GABA neurons. For each GABA_A subunit, the background shading marks the cortical layers where the indicated change in expression of that subunit was found. The lower expression of α1 and β2 mRNAs in layers 3 and 4 match that of the presynaptic alterations in PV basket cells. The increase in α2 expression in layer 2 is consistent with previous findings of pre- and post-synaptic alterations in chandelier cell inputs to the axon initial segment of pyramidal cells in this location[7]. In contrast, the absence of alterations in α3 subunit expression, which is present post-synaptic to chandelier cells in pyramidal neurons in layers 5–6, matches the failure to find significant changes in chandelier cell markers in these layers. The lower α5 subunit expression was observed in the deeper layers of the DLPFC where the somata of pyramidal neurons whose apical dendrites are known to be innervated by SST+ Martinotti cells, thought also to be affected in schizophrenia[72;73], are predominantly located. Adapted from [67].

Figure 3

Hypothesized model of the interactions between chloride (Cl⁻) transporters (NKCC1 and KCC2) and two kinases (OXSR1 and WNK3) that regulate their activity via phosphorylation. In both panels, the orange bar represents the cell membrane, with the extracellular domain above and the intracellular domain below the bar. The size and orientation of the green arrows indicates the magnitude and direction of Cl⁻ ion flow mediated by NKCC1, KCC2 and GABA_A receptor Cl⁻ channels. (A) In normal adult neurons, intracellular Cl⁻ concentration is low due to low levels of NKCC1 and high levels of KCC2. The binding of GABA to GABA_A receptors triggers Cl⁻ entry and membrane hyperpolarization. (B) In schizophrenia, increased OXSR1 and WNK3 kinase levels lead to increased phosphorylation (P) of both chloride transporters and consequently increased NKCC1 activity and decreased KCC2 activity, producing a greater intracellular Cl⁻ concentration. Thus, when GABA_A receptors are activated, Cl⁻ influx is reduced and GABA neurotransmission is less hyperpolarizing. Adapted from [69].