Anti-epileptogenic role of mTOR activation among hippocampal interneurons

项目摘要 癫痫可以是一种使人衰弱的，有时甚至是致命的疾病， 治愈，现有药物在三分之一的患者中失败。预防性治疗的发展 癫痫是一个关键的NINDS目标（基准II。预防癫痫及其进展; Galanopoulou等人， 2016; Binder等人，2020年）。雷帕霉素（mTOR）通路的机制靶点已成为一种有前途的 癫痫病预防目标。mTOR作为细胞生长的相对普遍的启动子;增强 神经元连接性、兴奋性和代谢。mTOR通路的激活发生在 癫痫发生，并似乎调节前兴奋的变化牵连的过程。此外，阻挡 mTOR信号传导与拮抗剂雷帕霉素在许多癫痫模型中减轻癫痫发展。 然而，阻断mTOR信号传导并不适用于所有模型，有证据表明，这一途径可能 还能降低大脑的兴奋性为了解释这些相互矛盾的效应，我们假设mTOR增加 兴奋性神经元之间的激活是致痫性的，而GABA能中间神经元之间的激活是致痫性的。 抗癫痫药因此，全身性mTOR拮抗剂阻断兴奋性神经元之间的致痫性变化， 细胞，但也阻止中间神经元之间的补偿性保护变化。为了验证这个假设，我们将使用 选择性删除专性mTOR调节蛋白Raptor或Rictor的交叉遗传方法 从囊泡GABA转运蛋白，小清蛋白，和生长抑素表达的小鼠中间神经元。我们将 我们还研究了通过删除mTOR负性基因来增强中间神经元中mTOR信号传导的影响。 调节器Tsc 2。将使用获得性和遗传性癫痫模型进行研究。我们预测 阻断中间神经元中的mTOR信号传导将使癫痫恶化，而增强信号传导将改善癫痫发作。 成果。研究将促进对mTOR在癫痫发生中的作用的理解，并将直接影响癫痫的发生。 对mTOR拮抗剂正在进行的临床使用的影响。

PROJECT SUMMARY Epilepsy can be a debilitating and sometimes fatal disease for which there are no preventatives, no cure, and for which existing medications fail in one third of patients. Development of preventative treatments for epilepsy is a key NINDS goal (Benchmark II. Prevent epilepsy and its progression; Galanopoulou et al., 2016; Binder et al., 2020). The mechanistic target of rapamycin (mTOR) pathway has emerged as a promising target for epilepsy prevention. mTOR acts as a relatively ubiquitous promotor of cell growth; enhancing neuronal connectivity, excitability and metabolism. Activation of the mTOR pathway occurs during epileptogenesis and appears to regulate pro-excitatory changes implicated in the process. Moreover, blocking mTOR signaling with the antagonist rapamycin mitigates epilepsy development in many epilepsy models. Blocking mTOR signaling, however, does not work in all models, and there is evidence that this pathway may also act to reduce brain excitability. To explain these conflicting effects, we hypothesize that increased mTOR activation among excitatory neurons is pro-epileptogenic, while activation among GABAergic interneurons is anti-epileptogenic. Systemic mTOR antagonists, therefore, block epileptogenic changes among excitatory cells, but also block compensatory protective changes among interneurons. To test this hypothesis, we will use intersectional genetic approaches to selectively delete the obligate mTOR regulatory proteins Raptor or Rictor from vesicular GABA transporter-, parvalbumin-, and somatostatin-expressing interneurons in mice. We will also examine the impact of enhancing mTOR signaling in interneurons by deleting the mTOR negative regulator Tsc2. Studies will be conducted using both acquired and genetic models of epilepsy. We predict that blocking mTOR signaling in interneurons will make epilepsy worse, while enhancing signaling will improve outcomes. Studies will advance understanding of the role of mTOR in epileptogenesis and will have direct implications for ongoing clinical use of mTOR antagonists.