结节性硬化症(TSC)是由TSC1或TSC2基因中的杂合突变引起的常染色体显性疾病。TSC通常与神经系统有关,认知,和行为缺陷。TSC患者还表现出与焦虑和情绪障碍的合并症。TSC的发病机制尚不完全清楚,但与TSC相关的神经系统症状伴随着过度的谷氨酸能活动和突触脊柱结构的改变。为了解决突触外(e)NMDA型谷氨酸受体(NMDAR)拮抗剂,与阻断生理阶段性突触活动的拮抗剂相反,可以改善这种疾病的突触和行为特征,我们利用TSC的Tsc2+/-小鼠模型来测量生化,电生理学,组织学,和小鼠的行为参数。我们发现在eNMDAR中发现的优先阻断补品活性的拮抗剂,特别是较新的药物NitroSynapsin,提供Tsc2+/-表型的生物学和统计学上的显着改善。伴随这种改善的是p38MAPK-TSC-Rheb-mTORC1-S6K1途径中活性的校正。海马长时程增强(LTP)的缺陷,突触的组织学损失,用NitroSynapsin治疗后,Tsc2+/-小鼠的行为恐惧条件均得到改善。一起来看,这些结果表明,过度激励的改善,通过限制异常的eNMDAR活性,可能代表了一种新的TSC治疗方法。
Tuberous sclerosis (TSC) is an autosomal dominant disorder caused by heterozygous mutations in the TSC1 or TSC2 gene. TSC is often associated with neurological, cognitive, and behavioral deficits. TSC patients also express co-morbidity with anxiety and mood disorders. The mechanism of pathogenesis in TSC is not entirely clear, but TSC-related neurological symptoms are accompanied by excessive glutamatergic activity and altered synaptic spine structures. To address whether extrasynaptic (e)NMDA-type glutamate receptor (NMDAR) antagonists, as opposed to antagonists that block physiological phasic synaptic activity, can ameliorate the synaptic and behavioral features of this disease, we utilized the Tsc2+/- mouse model of TSC to measure biochemical, electrophysiological, histological, and behavioral parameters in the mice. We found that antagonists that preferentially block tonic activity as found at eNMDARs, particularly the newer drug NitroSynapsin, provide biological and statistically significant improvement in Tsc2+/- phenotypes. Accompanying this improvement was correction of activity in the p38 MAPK-TSC-Rheb-mTORC1-S6K1 pathway. Deficits in hippocampal long-term potentiation (LTP), histological loss of synapses, and behavioral fear conditioning in Tsc2+/- mice were all improved after treatment with NitroSynapsin. Taken together, these results suggest that amelioration of excessive excitation, by limiting aberrant eNMDAR activity, may represent a novel treatment approach for TSC.