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

探索性测定 L 型钙通道在介导早期癫痫发作后异常可塑性和行为中的作用

• 批准号: 9454781
• 负责人: TIMOTHY A BENKE
• 金额: $ 18.99万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9454781
• 关键词: ARHGEF5 gene; Address; Age; Anatomy; Behavior; Behavioral; Binding; Biochemistry; Biological Markers; Cattle; Cells; Childhood; Chronic; Clinical; Clinical Research; Data; Development; Early treatment; Epilepsy; FMRP; FRAP1 gene; Functional disorder; Future; Genetic; Genetic Models; Hippocampus (Brain); Hyperactive behavior; Immunohistochemistry; In Vitro; Injury; Intellectual functioning disability; Isradipine; L-Type Calcium Channels; Life; Link; Long-Term Depression; Long-Term Potentiation; Measurement; Measures; Mediating; Modeling; Neurocognition; Neurocognitive; Neurocognitive Deficit; Pathway interactions; Patients; Peptides; Peritoneum; Pharmacology; Play; Protein phosphatase; Proteins; Publishing; Rattus; Rodent Model; Role; Seizures; Signal Transduction; Slice; Synaptic plasticity; Syndrome; Testing; Work; autism spectrum disorder; base; behavioral study; epileptic encephalopathies; experimental study; immunocytochemistry; improved; kainate; novel; novel therapeutics; protein protein interaction; secondary outcome; therapeutic target

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.

摘要：“探索性测定 L 型钙通道在介导异常可塑性中的作用 以及早期癫痫发作后的行为” 小儿癫痫性脑病 (P-EE) 综合征，其特征是频繁的早期癫痫发作 (ELS)， 与灾难性神经认知障碍有关，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，领导临床意见 该领域的看法差异很大，有些人认为 ELS 雪上加霜，并倾向于积极的治疗 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，并且有 没有疗法可以解决 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）这个可以治疗吗？ 我们假设高度活跃的 L 型钙通道 (LTCC) 在介导 P-EE 中的异常可塑性和行为。 CA1 海马切片的体外研究将药理学 比较长期发育的 LTCC 介导的突触可塑性 (SA1) 的机械变化 (P60+) ELS 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。我们的理由是，这些研究将继续寻找受机械启发的新颖疗法 与 ELS 相关的神经认知缺陷，但不存在可以提供显着社会效益的情况。 具体目标 1 (SA1)：从机制上将 KA-ELS 介导的 LTCC 功能障碍与关键 LTCC 破坏联系起来 影响 mGluR-LTD 的蛋白质-蛋白质相互作用。 具体目标 2 (SA2)：确定长期 LTCC 拮抗作用是否可以改善神经认知障碍 KA-ELS 后。 这些探索性研究将为进一步调查该问题的综合研究奠定基础。 LTCC 在介导 P-EE 和 ELS 神经认知缺陷中的机制作用。通过了解 LTCC 在 ELS (SA1) 后如何调节可塑性并确定是否是广谱 LTCC 抑制改善神经认知（SA2），然后我们可以推进 LTCC 相关的神经治疗策略 在 P-EE 和 ELS 遗传模型中的应用，将在未来的研究中进行表征。这些研究是 至关重要，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问题 ELS 的后果。