Exploratory determination of the role of L-type calcium channels in mediating abnormal plasticity and behavior after early life seizures

摘要：“探索性确定L型钙通道在介导异常可塑性中的作用 和早期癫痫发作后的行为” 小儿癫痫性脑病（P-EE）综合征，以频繁的早期癫痫发作（ELS）为特征， 与灾难性的神经认知障碍有关，包括自闭症谱系障碍和智力障碍。 自闭症（ASD/ID）。P-EE可能与损伤或遗传原因有关。目前，领导临床意见 在该领域的差异很大，有些人认为ELS增加了伤害的侮辱，并赞成积极的治疗 的ELS。对于我们的大多数患者来说，“牛已经出了谷仓”：ELS已经发生， 没有治疗方法来解决ELS本身的长期后果。因此，迫切需要 用啮齿动物模型研究这些问题：1）机制是什么？2)这可以治疗吗？ 我们推测，过度活跃的L型钙通道（LTCCs）在介导细胞凋亡中起重要作用。 在体外对CA 1海马脑片的研究将证实P-EE的可塑性和行为异常。 比较慢性发展的LTCC介导的突触可塑性（SA 1）的机制变化 (P60+）ELS之后。行为研究（SA 2）将确定LTCC拮抗剂的神经认知益处， ELS。我们的理由是，这些研究将继续机制启发，新的治疗方法， 与ELS相关的神经认知缺陷，其中不存在可以提供显著社会效益的缺陷。 具体目标1（SA 1）：将KA-ELS介导的LTCC功能障碍与关键LTCC的破坏机制联系起来 影响mGluR-LTD的蛋白质间相互作用。 具体目标2（SA 2）：确定慢性LTCC拮抗剂是否改善神经认知障碍 在KA-ELS之后。 这些探索性研究将为深入开展全面研究奠定基础， LTCC在ELS介导P-EE神经认知缺陷中的机制作用。通过了解 LTCC如何在ELS（SA 1）后机制性地调节可塑性，并确定广谱LTCC是否 抑制改善神经认知（SA 2），我们可以推进LTCC相关的神经治疗策略， P-EE与ELS的遗传模型的应用，在未来的研究中进行表征。这些研究 这是必要的，因为P-EE中的遗传或其他蛋白质替代策略可能不足以纠正长期 的后果。

ABSTRACT: “Exploratory determination of the role of L-type calcium channels in mediating abnormal plasticity and behavior after early life seizures” Pediatric epileptic encephalopathy (P-EE) syndromes, characterized by frequent early-life seizures (ELS), are associated with catastrophic neurocognitive impairment including autism spectrum disorder and intellectual disability (ASD/ID). P-EE can be associated with injury or genetic causes. Currently, clinical opinions by leaders vary widely in the field, with some believing that ELS adds insult to injury and favoring the aggressive treatment of ELS. For most of our patients, “the cow is already out of the barn”: ELS has already happened and there are no therapies to address the long-term consequences of ELS itself. Therefore, there is an urgent need to investigate these issues with rodent models: 1) What are the mechanisms? 2) Can this be treated? We hypothesize that hyperactive L-type calcium channels (LTCCs) play a substantial role to mediate abnormal plasticity and behavior in P-EE. Studies in CA1 hippocampal slices in vitro will pharmacologically compare mechanistic changes in synaptic plasticity (SA1) mediated by LTCCs that have developed chronically (P60+) after ELS. Behavioral studies (SA2) will determine the neurocognitive benefit of an LTCC antagonist after ELS. Our rationale is that these studies will segue to mechanistically inspired, novel therapeutics for neurocognitive deficits associated with ELS where none exist that could provide significant societal benefit. Specific Aim 1 (SA1): Mechanistically link KA-ELS-mediated LTCC dysfunction to disruption of key LTCC protein-protein interactions that impact mGluR-LTD. Specific Aim 2 (SA2): Determine whether chronic LTCC antagonism ameliorates neurocognitive impairment after KA-ELS. These exploratory studies will lay the groundwork to segue into comprehensive studies investigating the mechanistic roles of LTCC in mediating neurocognitive deficits in P-EE with ELS. By understanding mechanistically how LTCC modulate plasticity after ELS (SA1) and determining whether broad-spectrum LTCC inhibition improves neurocognition (SA2), we can then advance LTCC-related neurotherapeutic strategies for application to genetic models of P-EE with ELS, to be characterized in future studies. These studies are essential, as genetic or other protein replacement strategies in P-EE may be insufficient to correct the long-term consequences of ELS.