兴奋性突触后电位
基因敲除
海马结构
树突棘
神经科学
损失函数
基因剔除小鼠
突触
神经传递
海马体
生物
抑制性突触后电位
表型
受体
遗传学
基因
作者
Jiangxia Ni,Yongfei Ren,Tonghui Su,Jia Zhou,Chaoying Fu,Yi Lu,Dean Li,Jing Zhao,Yunxia Li,Yaoyang Zhang,Yanshan Fang,Nan Liu,Yang Geng,Yelin Chen
标识
DOI:10.1038/s41380-021-01346-0
摘要
TDP-43 proteinopathy is linked to neurodegenerative diseases that feature synaptic loss in the cortex and hippocampus, although it remains unclear how TDP-43 regulates mature synapses. We report that, in adult mouse hippocampus, TDP-43 knockdown, but not overexpression, induces robust structural and functional damage to excitatory synapses, supporting a role for TDP-43 in maintaining mature synapses. Dendritic spine loss induced by TDP-43 knockdown is rescued by wild-type TDP-43, but not ALS/FTLD-associated mutants, suggesting a common TDP-43 functional deficiency in neurodegenerative diseases. Interestingly, M337V and A90V mutants also display dominant negative activities against WT TDP-43, partially explaining why M337V transgenic mice develop hippocampal degeneration similar to that in excitatory neuronal TDP-43 knockout mice, and why A90V mutation is associated with Alzheimer's disease. Further analyses reveal that a TDP-43 knockdown-induced reduction in GluN2A contributes to synaptic loss. Our results show that loss of TDP-43 function underlies hippocampal and cortical synaptic degeneration in TDP-43 proteinopathies.
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