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：“探究l型钙通道在介导异常可塑性中的作用