Activation of TLR7-mediated autophagy increases epileptic susceptibility via reduced KIF5A-dependent GABA(A) receptor transport in a murine model

作者全名："Liu, Jing; Ke, Pingyang; Guo, Haokun; Gu, Juan; Liu, Yan; Tian, Xin; Wang, Xuefeng; Xiao, Fei"

作者地址："[Liu, Jing; Ke, Pingyang; Guo, Haokun; Gu, Juan; Liu, Yan; Tian, Xin; Wang, Xuefeng; Xiao, Fei] Chongqing Med Univ, Affiliated Hosp 1, Chongqing Key Lab Neurol, Dept Neurol, 1 Youyi Rd, Chongqing 400016, Peoples R China; [Liu, Jing] Chongqing Univ Three Gorges Hosp, Dept Neurol, 165 Xincheng Rd, Chongqing 404100, Peoples R China; [Xiao, Fei] Chongqing Med Univ, Inst Brain Sci & Dis, Chongqing 400016, Peoples R China"

通信作者："Wang, XF; Xiao, F (通讯作者)，Chongqing Med Univ, Affiliated Hosp 1, Chongqing Key Lab Neurol, Dept Neurol, 1 Youyi Rd, Chongqing 400016, Peoples R China.; Xiao, F (通讯作者)，Chongqing Med Univ, Inst Brain Sci & Dis, Chongqing 400016, Peoples R China."

来源：EXPERIMENTAL AND MOLECULAR MEDICINE

ESI学科分类：BIOLOGY & BIOCHEMISTRY

WOS号：WOS:000999345000011

JCR分区：Q1

影响因子：9.5

年份：2023

卷号：　

期号：　

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结束页：　

文献类型：Article; Early Access

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摘要："The pathophysiological mechanisms underlying epileptogenesis are poorly understood but are considered to actively involve an imbalance between excitatory and inhibitory synaptic transmission. Excessive activation of autophagy, a cellular pathway that leads to the removal of proteins, is known to aggravate the disease. Toll-like receptor (TLR) 7 is an innate immune receptor that regulates autophagy in infectious and noninfectious diseases. However, the relationship between TLR7, autophagy, and synaptic transmission during epileptogenesis remains unclear. We found that TLR7 was activated in neurons in the early stage of epileptogenesis. TLR7 knockout significantly suppressed seizure susceptibility and neuronal excitability. Furthermore, activation of TLR7 induced autophagy and decreased the expression of kinesin family member 5 A (KIF5A), which influenced interactions with gamma-aminobutyric acid type A receptor (GABA(A)R)-associated protein and GABA(A)R beta 2/3, thus producing abnormal GABA(A)R-mediated postsynaptic transmission. Our results indicated that TLR7 is an important factor in regulating epileptogenesis, suggesting a possible therapeutic target for epilepsy. Epilepsy: a receptor protein that can take a tollStudies using a mouse model of epilepsy implicate a protein inside cells called Toll-like receptor 7 (TLR7) in susceptibility to epileptic seizures, suggesting the protein could be a target for antiepileptic drugs. TLR7 is part of the immune system and is found in the external and internal membranes of some cells, recognizing molecules associated with infection and disease. It can, however, lead to damaging over-reactions, including auto-immune responses. Fei Xiao, Xuefeng Wang, and colleagues at Chongqing Medical University in China detected activation of TLR7 in mouse neurons during the cellular changes that underly a susceptibility to epilepsy. They also identified molecular signaling pathways allowing TLR7 activity to disturb nerve transmission by modulating processes that normally degrade used cell components. TLR7 and related proteins may also be involved in other noninfectious diseases of the central nervous system."

基金机构："Natural Science Foundation of Chongqing [CSTB2022NSCQ-MSX0747, cstc2021ycjh-bgzxm0035]; National Natural Science Foundation of China [81922023, 82271496, 82001378]; Science and Technology Research Program of Chongqing Education Commission [KJQN202200435]; Chongqing Talents: Exceptional Young Talents Project [CQYC202005014]; Future Medical Youth Innovation Team Program of Chongqing Medical University [W0043]; Fifth Senior Medical Talents Program of Chongqing for Young and Middle-aged, Middle-aged Medical Excellence Team Program of Chongqing; Chongqing chief expert studio project, China"

基金资助正文："This work was supported by the Natural Science Foundation of Chongqing (CSTB2022NSCQ-MSX0747, cstc2021ycjh-bgzxm0035), National Natural Science Foundation of China (No. 81922023, 82271496, and 82001378), Science and Technology Research Program of Chongqing Education Commission (KJQN202200435), Chongqing Talents: Exceptional Young Talents Project (CQYC202005014), Future Medical Youth Innovation Team Program of Chongqing Medical University (No. W0043), Fifth Senior Medical Talents Program of Chongqing for Young and Middle-aged, Middle-aged Medical Excellence Team Program of Chongqing, and Chongqing chief expert studio project, China."