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Mechanisms of cellular, synaptic and circuit dysfunction in Kcnc1-related epileptic encephalopathy

Kcnc1相关癫痫性脑病的细胞、突触和回路功能障碍的机制

基本信息

批准号：
10424981
负责人：
Eric Ryan Wengert
金额：
$ 6.72万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10424981
关键词：
Action Potentials Address Ataxia Axon Behavior Behavioral Calcium Cells Cerebral cortex Characteristics Complex Dendrites Disease Electrophysiology (science)Epilepsy Event Exhibits Fellowship Frequencies Functional disorder Generations Genes Goals Image Impaired cognition Impairment In Vitro Individual Intellectual functioning disability Interneurons Ion Channel Knowledge Lead Light Link Measures Mediating Mentors Methodology Mus National Research Service Awards Neurodevelopmental Disorder Neurologic Neurons Neurosciences Optics Other Genetics Parvalbumins Pathogenesis Pathogenicity Patients Phenotype Physiological Physiology Potassium Potassium Channel Presynaptic Terminals Progressive Myoclonic Epilepsies Property Recovery Recurrence Research Research Personnel Role Seizures Sensory Sodium Channel Symptoms Synapses Synaptic Transmission Technical Expertise Techniques Testing Training Variant Vibrissae Voltage-Gated Potassium Channel Wild Type Mouse awake base biophysical properties calcium indicator career density early onset epileptic encephalopathies excitatory neuron experimental study hippocampal pyramidal neuron in vivo insight loss of function mouse model mutant nervous system disorder neural circuit neuronal cell body neuronal circuitry neuronal excitability neurotransmission novel patch clamp response synaptic inhibition therapy development two-photon voltage

项目摘要

PROJECT SUMMARY I am applying for this NRSA postdoctoral fellowship with the long-term career goal of becoming an independent investigator capable of leading a highly productive research lab in the field of neuroscience. Under the guidance of Dr. Ethan Goldberg and Dr. Doug Coulter, this mentored fellowship will provide me the conceptual and hands-on training required to achieve my goal and thrive in the scientific enterprise. Pathogenic variants in the gene KCNC1, which encodes the voltage-gated potassium channel subunit Kv3.1, lead to severe neurological disease including epilepsy. While most patient-derived variants are loss-of- function, the precise mechanisms by which impaired Kv3.1 function alters individual neuron physiology and neural circuit function to result in spontaneous seizures are unclear. Kv3.1 is prominently expressed in parvalbumin-positive fast-spiking inhibitory interneurons (PV-IN) in various subcellular regions including the dendrites, soma, axon, and synaptic terminal where it critically contributes to reliable high-frequency action potential generation and propagation. Because PV-INs critically contribute to network dynamics and constrain excitability of nearby excitatory pyramidal neurons in cortical circuits, we hypothesize that Kv3.1 dysfunction impairs PV-IN high-frequency action potential generation and propagation, disinhibits pyramidal neurons, and contributes to aberrant network excitability to drive abnormal behavior and seizures. Therefore, the overarching objective of this study is to determine the effect of mutant Kv3.1 on PV-IN physiology as a potential major contributor to pathogenesis of KCNC1-related epilepsy. In aim 1, I will collect patch-clamp electrophysiology recordings of somatic and axonal potassium channel function and neuronal excitability in PV-INs from a novel mouse model of KCNC1 epilepsy which harbors the epileptic encephalopathy patient-derived p.A421V variant. Given the substantially reduced channel activity observed in the p.A421V variant, and that Kv3 currents are necessary for fast-spiking physiology, I anticipate that PV-INs from the mouse model of KCNC1 epileptic encephalopathy will exhibit impaired action potential generation at the soma, and unreliable propagation through the axon. In aim 2, I will interrogate deficits in inhibitory synaptic transmission in response to mutant Kv3.1 expression using multiple (6-8) simultaneous recordings of synaptically-connected PV-INs and pyramidal neurons in cortical microcircuits. Lastly, in aim 3 I will corroborate my in vitro findings in the in vivo context through calcium-imaging of neuronal activity in awake, behaving mice. To relate neuronal activity to relevant behavior, I will examine the excitability of both cortical pyramidal neurons and PV-INs in response to sensory stimulation by whisker deflection and test the hypothesis that altered Kv3.1 function in PV-INs compromises network inhibition in vivo. Overall, completion of the aims described in this mentored fellowship will provide significant insight into the mechanisms of epilepsy in KCNC1-related disorders and deeper understanding of the contribution of Kv3 channels to PV-IN physiology in general.

项目总结