Mislocalisation of TDP-43 to the cytoplasm causes cortical hyperexcitability and reduced excitatory neurotransmission in the motor cortex
Mislocalisation of TDP-43 to the cytoplasm causes cortical hyperexcitability and reduced excitatory neurotransmission in the motor cortex
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DOI：
10.1111/jnc.15214
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发表时间：
2020-11-09
影响因子：
4.7
通讯作者：
Blizzard, Catherine A.
中科院分区：
文献类型：
--
作者：
Dyer, Marcus S.;Reale, Laura A.;Blizzard, Catherine A.
肌萎缩侧索硬化症 (ALS) 是一种慢性神经退行性疾病，其病理特征是 RNA 结合蛋白 TAR-DNA 结合蛋白 43 (TDP-43) 从细胞核错误定位到细胞质。运动皮层神经元兴奋性的变化和突触功能障碍是 ALS 患者和小鼠疾病模型中发生的早期病理变化。为了研究错误定位的 TDP-43 对运动皮层神经元功能的影响，我们利用了在可诱导启动子上表达人类野生型 (TDP-43(WT)) 或核定位序列缺陷 TDP-43 (TDP-43(Delta NLS)) 的小鼠模型，该启动子丰富了前脑神经元的表达。通过免疫组织化学和全细胞膜片钳电生理学研究病理生理学。成年小鼠中 TDP-43(Delta NLS) 表达 30 天不会引起运动皮层 CTIP2 阳性神经元数量的任何变化。然而，在这个时间点，TDP-43(Delta NLS) 的表达驱动运动皮层 V 层兴奋性神经元的内在过度兴奋。这种过度兴奋性伴随着这些细胞的兴奋性突触输入的减少以及离子型谷氨酸受体的两个方向的波动而发生。 TDP-43(WT) 表达不存在这种病理生理学，这表明 TDP-43 定位到细胞质对于改变兴奋性表型至关重要。这项研究对于与 ALS 相关的最臭名昭著的蛋白质之一 TDP-43 的毒性机制具有重要意义。我们提供了第一个证据，证明 TDP-43 错误定位会导致运动皮层突触功能异常和过度兴奋表型，将 ALS 患者出现的一些最早的功能障碍与 TDP-43 错误定位联系起来。
Amyotrophic lateral sclerosis (ALS) is a chronic neurodegenerative disease pathologically characterised by mislocalisation of the RNA-binding protein TAR-DNA-binding protein 43 (TDP-43) from the nucleus to the cytoplasm. Changes to neuronal excitability and synapse dysfunction in the motor cortex are early pathological changes occurring in people with ALS and mouse models of disease. To investigate the effect of mislocalised TDP-43 on the function of motor cortex neurons we utilised mouse models that express either human wild-type (TDP-43(WT)) or nuclear localisation sequence-deficient TDP-43 (TDP-43(Delta NLS)) on an inducible promoter that enriches expression to forebrain neurons. Pathophysiology was investigated through immunohistochemistry and whole-cell patch-clamp electrophysiology. Thirty days expression of TDP-43(Delta NLS) in adult mice did not cause any changes in the number of CTIP2-positive neurons in the motor cortex. However, at this time-point, the expression of TDP-43(Delta NLS) drives intrinsic hyperexcitability in layer V excitatory neurons of the motor cortex. This hyperexcitability occurs concomitantly with a decrease in excitatory synaptic input to these cells and fluctuations in both directions of ionotropic glutamate receptors. This pathophysiology is not present with TDP-43(WT) expression, demonstrating that the localisation of TDP-43 to the cytoplasm is crucial for the altered excitability phenotype. This study has important implications for the mechanisms of toxicity of one of the most notorious proteins linked to ALS, TDP-43. We provide the first evidence that TDP-43 mislocalisation causes aberrant synaptic function and a hyperexcitability phenotype in the motor cortex, linking some of the earliest dysfunctions to arise in people with ALS to mislocalisation of TDP-43.