GluN2D-mediated excitatory drive onto medial prefrontal cortical PV+ fast-spiking inhibitory interneurons.

Jonathan Garst-Orozco,Mark L Weber,Vikaas S Sohal,Derek L Buhl,Dominique Arion,Patricio O’Donnell,Thomas A Lanz,Hualin Xi,David A Lewis,John F Enwright,Ruchi Malik,Pavel I Ortinski

doi:10.1371/journal.pone.0233895

Abstract

Deficits in fast-spiking inhibitory interneurons (FSINs) within the dorsolateral prefrontal cortex (dlPFC) are hypothesized to underlie cognitive impairment associated with schizophrenia. Though representing a minority of interneurons, this key cell type coordinates broad neural network gamma-frequency oscillations, associated with cognition and cognitive flexibility. Here we report expression of GluN2D mRNA selectively in parvalbumin positive cells of human postmortem dlPFC tissue, but not pyramidal neurons, with little to no GluN2C expression in either cell type. In acute murine mPFC slices the GluN2C/D selective positive allosteric modulator (PAM), CIQ(+), increased the intrinsic excitability as well as enhanced NMDAR-mediated EPSCs onto FSINs. This increase in intrinsic excitability with GluN2C/D PAM was also observed in the Dlx 5/6+/- FSIN developmental deficit model with reported FSIN hypoexcitability. Together these data speak to selective modulation of FSINs by a GluN2D PAM, providing a potential mechanism to counter the FSIN-deficit seen in schizophrenia.

Highlights

Studies of the underlying pathophysiology of schizophrenia have led to the NMDA, GABA and dopaminergic hypotheses, backed by pharmacological manipulations that replicate key aspects of the pathology
The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
Reduced expression of GAD67 protein has been found in parvalbumin interneuron terminals [31], and a reduction in mean parvalbumin intensity has been measured in parvalbumin interneurons in schizophrenia without an alteration in PV neuron density [32]

Summary

Introduction

Studies of the underlying pathophysiology of schizophrenia have led to the NMDA, GABA and dopaminergic hypotheses, backed by pharmacological manipulations that replicate key aspects of the pathology. The dopamine (DA) hypothesis, which has remained the most. GluN2D-mediated excitatory input onto medial prefrontal cortical FSINs. to publish, or preparation of the manuscript. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are listed in the ‘author contribution’ section

Methods

Results

Conclusion