Modulation of Hippocampal GABAergic Neurotransmission and Gephyrin Levels by Dihydromyricetin Improves Anxiety.

Daniel P Holschneider,Richard W Olsen,Jing Liang,Xuesi M Shao,Joshua Silva,Daryl L Davies,Yi Shen,Amy S Shao

doi:10.3389/fphar.2020.01008

Abstract

Anxiety disorders are the most common mental illness in the U.S. and are estimated to consume one-third of the country’s mental health spending. Although anxiolytic therapies are available, many patients exhibit treatment-resistance, relapse, or substantial side effects. An urgent need exists to explore the underlying mechanisms of chronic anxiety and to develop alternative therapies. Presently, we identified dihydromyricetin (DHM), a flavonoid that has anxiolytic properties in a mouse model of isolation-induced anxiety. Socially isolated mice demonstrated increased anxiety levels and reduced exploratory behavior measured by elevated plus-maze and open-field tests. Socially isolated mice showed impaired GABAergic neurotransmission, including reduction in GABAA receptor-mediated extrasynaptic tonic currents, as well as amplitude and frequency of miniature inhibitory postsynaptic currents measured by whole-cell patch-clamp recordings from hippocampal slices. Furthermore, intracellular ATP levels and gephyrin expression decreased in anxious animals. DHM treatment restored ATP and gephyrin expression, GABAergic transmission and synaptic function, as well as decreased anxiety-like behavior. Our findings indicate broader roles for DHM in anxiolysis, GABAergic neurotransmission, and synaptic function. Collectively, our data suggest that reduction in intracellular ATP and gephyrin contribute to the development of anxiety, and represent novel treatment targets. DHM is a potential candidate for pharmacotherapy for anxiety disorders.

Highlights

Anxiety disorders are a group of mental disorders and a leading cause of disability in Western societies (Craske et al, 2017)
Mice with 2 weeks of DZ administration after 4 weeks of isolation (Iso4+DZ2) spent less time in the open arm and more time in the closed arm in comparison to DHM treatment group. These results suggest that social isolation increases anxiety levels, and is impacted by the timeframe of social isolation
We found that social isolation of C57BL/6J mice (a) increased anxiety-like behavior; (b) impaired synaptic and extrasynaptic GABAergic inhibitory neurotransmission; (c) reduced hippocampal ATP levels and gephyrin expression, and (d) these behavioral deficits, and cellular and molecular impairments were attenuated with DHM administration

Summary

Introduction

Anxiety disorders are a group of mental disorders and a leading cause of disability in Western societies (Craske et al, 2017). Anxiety disorders, including generalized anxiety disorder, panic disorder, social anxiety disorder, obsessive-compulsive disorder, posttraumatic stress disorders, and phobias, typically have an early onset, run a chronic or relapsing course, cause substantial personal distress, impair social and occupational function, reduce quality of life, and impose a substantial economic burden (Kessler et al, 2005; Toghanian et al, 2014). These disorders cost the U.S more than $42 billion a year, comprising almost one-third of the country’s total mental health bill allotment (Sinoff and Werner, 2003; Merikangas et al, 2010). New treatment strategies are needed that are capable of effectively and safely treating anxiety disorders with consistent effects, reduced rates of relapse, and fewer adverse side effects

Objectives

Methods

Results

Conclusion