2. Academic Validation
  3. Long noncoding RNA Gm2694 drives depressive-like behaviors in male mice by interacting with GRP78 to disrupt endoplasmic reticulum homeostasis

Long noncoding RNA Gm2694 drives depressive-like behaviors in male mice by interacting with GRP78 to disrupt endoplasmic reticulum homeostasis

  • Sci Adv. 2022 Dec 2;8(48):eabn2496. doi: 10.1126/sciadv.abn2496.
Hong-Sheng Chen 1 2 3,  Ji Wang 1,  Hou-Hong Li 1,  Xiao Wang 1,  Shao-Qi Zhang 1,  Tan Deng 1,  Yu-Ke Li 1,  Ruo-Si Zou 1,  Hua-Jie Wang 1,  Rui Zhu 1,  Wen-Long Xie 1,  Gang Zhao 4,  Fang Wang 1 2 3 5 6,  Jian-Guo Chen 1 2 3 5 6
Affiliations

Affiliations

  • 1 Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, China.
  • 2 The Research Center for Depression, Tongji Medical College, Huazhong University of Science, 430030 Wuhan, China.
  • 3 The Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province, 430030 Wuhan, China.
  • 4 Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022 Wuhan, China.
  • 5 The Key Laboratory of Neurological Diseases (HUST), Ministry of Education of China, 430030 Wuhan, China.
  • 6 Laboratory of Neuropsychiatric Diseases, The Institute of Brain Research, Huazhong University of Science and Technology, 430030 Wuhan, China.
PMID: 36459549 DOI: 10.1126/sciadv.abn2496
Abstract

Long noncoding RNAs (lncRNAs) are involved in various biological processes and implicated in the regulation of neuronal activity, but the potential role of lncRNAs in depression remains largely unknown. Here, we identified that lncRNA Gm2694 was increased in the medial prefrontal cortex (mPFC) of male mice subjected to chronic social defeat stress (CSDS). The down-regulation of Gm2694 in the mPFC alleviated CSDS-induced depressive-like behaviors through enhanced excitatory synaptic transmission. Furthermore, we found that Gm2694 preferentially interacted with the carboxyl-terminal domain of 78-kilodalton glucose-regulated protein (GRP78), which abrogated GRP78 function and disrupted endoplasmic reticulum homeostasis, resulting in a reduction of the surface expression of AMPA receptors (AMPARs). Overexpression of GRP78 in the mPFC promoted the surface expression of AMPARs and attenuated the CSDS-induced depressive-like behaviors of mice. Together, our results unraveled a previously unknown role of Gm2694 in regulating endoplasmic reticulum homeostasis and excitatory synaptic transmission in depression.

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