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

文摘：“L型钙通道在调节异常可塑性中作用的探索性测定 以及早年癫痫发作后的行为“ 儿童癫痫脑病(P-EE)综合征，以频繁的早期癫痫(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 残疾(ASD/ID)。P-EE可能与损伤或遗传原因有关。目前，领导的临床意见 在赛场上差异很大，一些人认为ELS增加了对伤病的侮辱，支持积极的治疗 ELS。对于我们的大多数患者来说，“牛已经出栏了”：ELS已经发生了，有 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)这是可以治疗的吗？ 我们推测，过度活跃的L型钙通道(LTCC)在钙离子通道的调节中起重要作用 P-EE的可塑性和行为异常。CA1海马片的体外药理学研究 比较慢性发育的LTCC介导的突触可塑性(SA1)的机械性变化 (P60+)在ELS之后。行为研究(SA2)将确定LTCC拮抗剂在治疗后的神经认知益处 ELS。我们的理论基础是，这些研究将转向机械启发的、新的治疗方法 与ELS相关的神经认知缺陷，如果不存在，可能会带来显著的社会利益。 特定目标1(SA1)：KA-ELS介导的LTCC功能障碍与关键LTCC中断的机械联系 影响mGluR-Ltd.的蛋白质-蛋白质相互作用。 特定目标2(SA2)：确定慢性LTCC拮抗剂是否改善神经认知功能障碍 在Ka-Els之后。 这些探索性研究将为深入研究 LTCC在ELS致P-EE神经认知功能障碍中的机制作用通过理解 LTCC如何调控ELS(SA1)后的塑性及确定广谱LTCC是否 抑制改善神经认知(SA2)，然后我们可以推进与LTCC相关的神经治疗策略 ELS在P-EE遗传模型中的应用，将在未来的研究中表征。这些研究是 必需的，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 ELS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.