Reduced Juvenile Long-Term Depression in Tuberous Sclerosis Complex Is Mitigated in Adults by Compensatory Recruitment of mGluR5 and Erk Signaling

Tuberous sclerosis complex (TSC) is a multisystem genetic disease that manifests with mental retardation, tumor formation, autism, and epilepsy. Heightened signaling through the mammalian target of rapamycin (mTOR) pathway is involved in TSC pathology, however it remains unclear how other signaling pathways are perturbed and contribute to disease symptoms. Reduced long-term depression (LTD) was recently reported in TSC mutant mice. We find that although reduced LTD is a feature of the juvenile mutant hippocampus, heightened expression of metabotropic glutamate receptor 5 and constitutively activated Erk signaling in the adult hippocampus drives wild-type levels of LTD. Increased mGluR5 and Erk results in a novel mTOR-independent LTD in CA1 hippocampus of adult mice, and contributes to the development of epileptiform bursting activity in the TSC2+/− CA3 region of the hippocampus. Inhibition of mGluR5 or Erk signaling restores appropriate mTOR-dependence to LTD, and significantly reduces epileptiform bursting in TSC2+/− hippocampal slices. We also report that adult TSC2+/− mice exhibit a subtle perseverative behavioral phenotype that is eliminated by mGluR5 antagonism. These findings highlight the potential of modulating the mGluR5-Erk pathway in a developmental stage-specific manner to treat TSC.结节性硬化症（Tuberous sclerosis complex, TSC）是一种多系统性遗传疾病，临床表现为智力障碍、肿瘤形成、自闭症及癫痫。哺乳动物雷帕霉素靶蛋白（mammalian target of rapamycin, mTOR）通路的信号过度激活参与了TSC的病理进程，但目前尚不清楚其他信号通路如何受到扰动并参与疾病症状的发生。近期有研究报道，TSC突变小鼠中存在长时程抑制（long-term depression, LTD）水平降低的现象。本研究发现，尽管长时程抑制水平降低是幼年突变小鼠海马体的特征之一，但成年海马体中代谢型谷氨酸受体5（metabotropic glutamate receptor 5）的表达上调与组成型激活的细胞外信号调节激酶（Extracellular signal-regulated kinase, Erk）信号通路，可使长时程抑制恢复至野生型水平。代谢型谷氨酸受体5与细胞外信号调节激酶的上调，在成年小鼠海马CA1区介导了一种新型的、不依赖mTOR的长时程抑制机制，并参与了TSC2+/−小鼠海马CA3区癫痫样爆发活动的发生发展。抑制代谢型谷氨酸受体5或细胞外信号调节激酶信号通路，可恢复长时程抑制对mTOR的正常依赖性，并显著降低TSC2+/−海马脑片中的癫痫样爆发活动。本研究还发现，成年TSC2+/−小鼠表现出轻微的持续性行为表型，该表型可通过代谢型谷氨酸受体5的拮抗作用消除。这些研究结果凸显了以发育阶段特异性方式调控代谢型谷氨酸受体5-细胞外信号调节激酶通路，以治疗TSC的潜在可能性。