Activation of LXRβ Signaling in the Amygdala Confers Anxiolytic Effects Through Rebalancing Excitatory and Inhibitory Neurotransmission upon Acute Stress

Wen Yu, Lu Wang, Le Yang, Yan Jiao Li, Min Wang, Chen Qiu, Qi Yang, Xu Bo Li, Yun Long Huang, Rui Liu, Yu Mei Wu

Research output: Contribution to journalArticle

Abstract

The balance of major excitatory (glutamate, Glu) and inhibitory (γ-aminobutyric acid, GABA), named as E/I neurotransmission, is critical for proper information processing. Anxiety-like responses upon stress are accompanied by abnormal alterations in the formation and function of synapses, resulting in the imbalance of E/I neurotransmission in the amygdala. Liver X receptors (LXRs), including LXRα and LXRβ isoforms, are nuclear receptors responsible for regulating central nervous system (CNS) functions besides maintaining metabolic homeostasis. However, little is known about the contribution of LXRs in E/I balance in regulating anxiety-related behaviors induced by stress. In this study, we found stress-induced anxiety led to the expression reduction of LXRβ not LXRα in mice amygdala. GW3965, a dual agonist for both LXRα and LXRβ, alleviated anxiety-like behaviors of stressed mice through activation of LXRβ, confirmed by the knockdown of LXRβ mediated by lentiviral shRNAs in the basolateral amygdala (BLA). This was paralleled by correcting the disequilibrium of E/I neurotransmission in the stressed BLA. Importantly, GW3965 exerted anxiolytic effects by correcting the promoted amplitude and frequency of miniature excitatory postsynaptic current (mEPSC), and augmenting the decreased that of miniature inhibitory postsynaptic current (mIPSC) in the stressed BLA. This suggests that stress-induced anxiety-like behaviors can largely be ascribed to the deficit of LXRβ signaling in E/I neurotransmission in BLA. These findings highlight the deficiency of LXRβ signaling in the amygdala linked to anxiety disorder, and LXRβ activation may represent a potential novel target for anxiety treatment with an alteration in synaptic transmission in the amygdala.

Original languageEnglish (US)
JournalNeurotherapeutics
DOIs
StateAccepted/In press - 2020

Keywords

  • E/I neurotransmission
  • GW3965
  • Liver X receptors
  • amygdala
  • anxiety

ASJC Scopus subject areas

  • Pharmacology
  • Clinical Neurology
  • Pharmacology (medical)

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