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：“探索性确定L型钙通道在介导异常可塑性中的作用 和早年癫痫发作后的行为” 小儿癫痫性脑病（P-EE）综合征，其特征是早期癫痫发作（ELS）， 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 残疾（ASD/ID）。 P-EE可以与伤害或遗传原因有关。目前，领导者的临床意见 在该领域的差异很大，有些信念认为EL会增加伤害并偏爱积极的治疗 Els。对于我们的大多数患者，“母牛已经不在谷仓里”：Els已经发生了，并且有 没有疗法来解决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）有什么机制？ 2）可以对此进行处理？ 我们假设多动激动的L型钙通道（LTCC）在调解中起着重要作用 P-EE中的可塑性和行为异常。在CA1海马切片中的研究将在体外进行药物 比较由LTCC介导的突触可塑性（SA1）的机械变化，这些LTCC已长期发展 （p60+）EL后。行为研究（SA2）将确定LTCC拮抗剂在 Els。我们的理由是，这些研究将促进机械灵感的新型疗法 神经认知定义了与EL相关的，而没有任何可以提供重大社会利益的EL。 特定目标1（SA1）：机械机械地将KA-ELS介导的LTCC功能障碍与钥匙LTCC的破坏联系起来 影响mglur-ltd的蛋白质蛋白相互作用。 特定目标2（SA2）：确定慢性LTCC拮抗作用是否可以改善神经认知障碍 在ka-els之后。 这些探索性研究将为研究研究的全面研究奠定基础 LTCC在与ELS的P-EE中介导神经认知缺陷中的机械作用。通过理解 LTCC如何调节ELS（SA1）后的可塑性并确定是否宽光谱LTCC来调节可塑性 抑制作用改善了神经认知（SA2），然后我们可以推进与LTCC相关的神经治疗策略 在未来的研究中将其应用于具有ELS的P-EE的遗传模型。这些研究是 必不可少的，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 EL的后果。