Long-Term Enhancement of NMDA Receptor Function in Inhibitory Neurons Preferentially Modulates Potassium Channels and Cell Adhesion Molecules.

Xiaoyan Ma,Xinyang Zhang,Dan Xia,Shaowen Bao,Jianzheng Wang,Di Deng,Samer Masri,Qiang Zhou,Songnian Hu

doi:10.3389/fphar.2021.796179

Abstract

Effectively enhancing the activity of inhibitory neurons has great therapeutic potentials since their reduced function/activity has significant contributions to pathology in various brain diseases. We showed previously that NMDAR positive allosteric modulator GNE-8324 and M-8324 selectively increase NMDAR activity on the inhibitory neurons and elevates their activity in vitro and in vivo. Here we examined the impact of long-term administering M-8324 on the functions and transcriptional profiling of parvalbumin-containing neurons in two representative brain regions, primary auditory cortex (Au1) and prelimbic prefrontal cortex (PrL-PFC). We found small changes in key electrophysiological parameters and RNA levels of neurotransmitter receptors, Na+ and Ca2+ channels. In contrast, large differences in cell adhesion molecules and K+ channels were found between Au1 and PrL-PFC in drug-naïve mice, and differences in cell adhesion molecules became much smaller after M-8324 treatment. There was also minor impact of M-8324 on cell cycle and apoptosis, suggesting a fine safety profile.

Highlights

Proper balance between excitation and inhibition (E/I) is critical to many vital functions of the brain and its alteration is believed to contribute to the pathogenesis of various brain diseases (Isaacson and Scanziani, 2011; Yizhar et al, 2011; Nelson and Valakh, 2015)
By using a combination of electrophysiological recordings and RNA-seq on PV-neurons, we found that key electrophysiological parameters and expression of glutamate receptors (GluRs), GABARs, Na+ channels, and Ca2+ channels were minimally altered by long-term M-8324 treatment or between different brain regions
To understand the impact of long-term enhancing NMDA-subtype glutamatergic receptors (NMDAR) and activity of GABAergic neurons in vivo, we recorded from genetically identified PV-neurons in brain slices from mice being treated with M-8324 for 7 days, recorded neuronal activity in vivo, and obtained RNAs from PV-neurons for RNA-seq analysis

Summary

Introduction

Proper balance between excitation and inhibition (E/I) is critical to many vital functions of the brain and its alteration is believed to contribute to the pathogenesis of various brain diseases (Isaacson and Scanziani, 2011; Yizhar et al, 2011; Nelson and Valakh, 2015). Long-Term NMDAR Enhancement on PV-Neurons spike at high frequencies and their critical contributions to working memory and gamma oscillation (Bartos et al, 2007; Sohal et al, 2009; Buzsaki and Wang, 2012) These PV-neurons provide powerful perisomatic inhibition to excitatory neurons to enable synchronized brain rhythmic activity between excitatory and inhibitory neurons within the neural network (Freund and Katona, 2007). Their dysfunction is well documented in the literature, from reduced PV expression (Filice et al, 2016; Xia et al, 2021), altered synaptic excitability (Xiao et al, 2020), to cell loss (Sakai et al, 2008; Du and Grace, 2016). How to maintain the proper functions of PV-neurons without compromising their health is a key issue to be addressed when improving their functions

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Conclusion