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.

TDP-43 蛋白病与以大脑皮层和海马体突触缺失为特征的神经退行性疾病有关，但目前尚不清楚 TDP-43 如何调节成熟突触。我们报告说，在成年小鼠海马体中，TDP-43 敲低而非过度表达会对兴奋性突触造成强烈的结构和功能损伤，支持 TDP-43 在维持成熟突触中的作用。由 TDP-43 敲低引起的树突棘损失被野生型 TDP-43 挽救，但不是 ALS/FTLD 相关突变体，表明神经退行性疾病中常见的 TDP-43 功能缺陷。有趣的是，M337V 和 A90V 突变体也显示出针对 WT TDP-43 的显性负活性，部分解释了为什么 M337V 转基因小鼠会出现类似于兴奋性神经元 TDP-43 敲除小鼠的海马退化，以及为什么 A90V 突变与阿尔茨海默病有关。进一步的分析表明，TDP-43 敲低诱导的 GluN2A 减少导致突触丢失。我们的结果表明，TDP-43 功能的丧失是 TDP-43 蛋白病中海马和皮质突触变性的基础。