Department of Neurological Surgery, Columbia University Irving Medical Center, New York, NY 10032, USA.
Department of Neurology, Columbia University Irving Medical Center, New York, NY 10032, USA.
Cell Rep. 2022 Jul 19;40(3):111085. doi: 10.1016/j.celrep.2022.111085.
Tuberous sclerosis complex (TSC) is a developmental disorder associated with epilepsy, autism, and cognitive impairment. Despite inactivating mutations in the TSC1 or TSC2 genes and hyperactive mechanistic target of rapamycin (mTOR) signaling, the mechanisms underlying TSC-associated neurological symptoms remain incompletely understood. Here we generate a Tsc1 conditional knockout (CKO) mouse model in which Tsc1 inactivation in late embryonic radial glia causes social and cognitive impairment and spontaneous seizures. Tsc1 depletion occurs in a subset of layer 2/3 cortical pyramidal neurons, leading to development of cytomegalic pyramidal neurons (CPNs) that mimic dysplastic neurons in human TSC, featuring abnormal dendritic and axonal overgrowth, enhanced glutamatergic synaptic transmission, and increased susceptibility to seizure-like activities. We provide evidence that enhanced synaptic excitation in CPNs contributes to cortical hyperexcitability and epileptogenesis. In contrast, astrocytic regulation of synapse formation and synaptic transmission remains unchanged after late embryonic radial glial Tsc1 inactivation, and astrogliosis evolves secondary to seizures.
结节性硬化症复合征（TSC）是一种与癫痫、自闭症和认知障碍相关的发育障碍。尽管 TSC1 或 TSC2 基因失活突变和机械性靶标雷帕霉素（mTOR）信号的过度活跃，但 TSC 相关神经症状的机制仍不完全清楚。在这里，我们生成了一种 Tsc1 条件性敲除（CKO）小鼠模型，其中 Tsc1 在晚期胚胎放射状胶质中的失活导致社会和认知障碍以及自发性癫痫发作。Tsc1 的耗竭发生在皮质 2/3 层的锥体神经元亚群中，导致巨细胞锥体神经元（CPN）的发育，其模拟人类 TSC 中的发育不良神经元，具有异常的树突和轴突过度生长、增强的谷氨酸能突触传递以及增加对癫痫样活动的易感性。我们提供的证据表明，CPN 中的增强的突触兴奋有助于皮质过度兴奋和癫痫发生。相比之下，晚期胚胎放射状胶质 Tsc1 失活后，星形胶质细胞对突触形成和突触传递的调节保持不变，并且星形胶质细胞增生继发于癫痫发作。
