Abstract

Stress negatively affects processes of synaptic plasticity and is a major risk factor of various psychopathologies such as depression and anxiety. HOMER1 is an important component of the postsynaptic density: constitutively expressed long isoforms HOMER1b and HOMER1c bind to group I metabotropic glutamate receptors MGLUR1 (GRM1) and MGLUR5 and to other effector proteins, thereby forming a postsynaptic protein scaffold. Activation of the GLUR1–HOMER1b,c and/or GLUR5–HOMER1b,c complex regulates activity of the NMDA and AMPA receptors and Ca²⁺ homeostasis, thus modulating various types of synaptic plasticity. Dominant negative transcript Homer1a is formed as a result of activity-induced alternative termination of transcription. Expression of this truncated isoform in response to neuronal activation impairs interactions of HOMER1b,c with adaptor proteins, triggers ligand-independent signal transduction through MGLUR1 and/or MGLUR5, leads to suppression of the AMPA- and NMDA-mediated signal transmission, and thereby launches remodeling of the postsynaptic protein scaffold and inhibits long-term potentiation. The studies on animal models confirm that the HOMER1a-dependent remodeling most likely plays an important part in the stress susceptibility, whereas HOMER1a itself can be regarded as a neuroprotector. In this review article, we consider the effects of different stressors in various animal models on HOMER1 expression as well as impact of different HOMER1 variants on human behavior as well as structural and functional characteristics of the brain.

中文翻译：

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应激诱导的 Homer1 表达变化在应激易感性中的作用

摘要

压力会对突触可塑性过程产生负面影响，并且是各种精神病理学（如抑郁和焦虑）的主要危险因素。HOMER1 是突触后密度的重要组成部分：组成型表达的长同种型 HOMER1b 和 HOMER1c 与 I 组代谢型谷氨酸受体 MGLUR1 (GRM1) 和 MGLUR5 以及其他效应蛋白结合，从而形成突触后蛋白支架。GLUR1–HOMER1b,c 和/或 GLUR5–HOMER1b,c 复合物的激活可调节 NMDA 和 AMPA 受体的活性以及 Ca ²⁺稳态，从而调节各种类型的突触可塑性。显性阴性转录本Homer1a是由于活性诱导的转录替代终止而形成的。响应神经元激活的这种截短同种型的表达会削弱 HOMER1b,c 与衔接蛋白的相互作用，通过 MGLUR1 和/或 MGLUR5 触发不依赖配体的信号转导，导致抑制 AMPA 和 NMDA 介导的信号传输，从而启动突触后蛋白支架的重塑并抑制长时程增强。对动物模型的研究证实，HOMER1a 依赖性重塑最有可能在应激易感性中起重要作用，而 HOMER1a 本身可被视为神经保护剂。在这篇评论文章中，