Activation of LXRβ signaling in amygdala confers anxiolytic effects through rebalancing excitatory and inhibitory neurotransmission upon acute stress.
Activation of LXRβ signaling in amygdala confers anxiolytic effects through rebalancing excitatory and inhibitory neurotransmission upon acute stress.
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杏仁核中 LXR β 信号传导的激活通过在急性应激时重新平衡兴奋性和抑制性神经传递来产生抗焦虑作用
DOI：
10.1007/s13311-020-00857-y
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发表时间：
--
影响因子：
5.7
通讯作者：
Wu Yu-Mei
中科院分区：
文献类型：
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作者：
Yu Wen;Wang Lu;Yang Le;Li Yan-Jiao;Wang Min;Qiu Chen;Yang Qi;Li Xu-Bo;Huang Yun-Long;Liu Rui;Wu Yu-Mei
主要兴奋性（谷氨酸，Glu）和抑制性（γ-氨基丁酸，GABA）的平衡，称为E/I神经传递，对正确的信息处理至关重要。应激时的类突触反应伴随着突触形成和功能的异常改变，导致杏仁核内E/I神经传递失衡。肝脏X受体（LXR）包括LXRα和LXRβ亚型，是一种核受体，除了维持代谢稳态外，还负责调节中枢神经系统（CNS）功能。然而，很少有人知道LXRs在E/I平衡调节焦虑相关行为的压力。本研究发现，应激诱导的焦虑导致小鼠杏仁核LXRβ表达降低，而LXRα表达降低。GW 3965是LXRα和LXRβ的双重激动剂，通过激活LXRβ减轻应激小鼠的焦虑样行为，这一点通过基底外侧杏仁核（BLA）中慢病毒shRNA介导的LXRβ敲减得到证实。这是通过纠正应激BLA中E/I神经传递的不平衡来实现的。更重要的是，GW 3965通过纠正应激BLA中微兴奋性突触后电流（mEPSC）的幅度和频率的升高，并增强微抑制性突触后电流（mIPSC）的降低而发挥抗焦虑作用。这表明应激诱导的焦虑样行为在很大程度上可归因于BLA中E/I神经传递中LXRβ信号转导的缺陷。这些发现强调了与焦虑症相关的杏仁核中LXRβ信号传导的缺陷，并且LXRβ激活可能代表了通过改变杏仁核中的突触传递来治疗焦虑症的潜在新靶点。
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.