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Interneuron axonopathy underlies circuit dysfunction in a mouse model of Dravet syndrome

中间神经元轴突病变是 Dravet 综合征小鼠模型中回路功能障碍的基础

基本信息

批准号：
9910475
负责人：
ETHAN M GOLDBERG
金额：
$ 44.29万
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：
2019
资助国家：
美国
起止时间：
2019-04-15 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9910475
关键词：
Action Potentials Acute Affect Anatomy Animal Model Axon Biological Models Brain Brain imaging Calcium Cell Transplantation Cells Cerebral cortex Cerebrum Child Clinical Closure by clamp Data Development Developmental Delay Disorders Diagnosis Disease Distal Electroencephalography Electrophysiology (science)Epilepsy Experimental Animal Model Experimental Models Failure Frequencies Functional disorder Future Generations Gene Mutation Generations Genes Goals Human Image Immunohistochemistry Impairment In Vitro Intellectual functioning disability Interneurons Ion Channel Knowledge Lateral Maps Measures Medical Genetics Membrane Molecular Mus Mutation Neurodevelopmental Disorder Neurons Neurosciences Outcome Parvalbumins Pathogenesis Pathology Patient Care Patient-Focused Outcomes Patients Pattern Physiological Physiology Property Pyramidal Cells Quality of life Recovery Regulation Research Research Personnel Resistance Role Seizures Sensory Severities Site Slice Sodium Somatosensory Cortex Somatostatin Sudden Death Synapses Testing Time Up-Regulation Validation Vibrissae Whole-Cell Recordings Wild Type Mouse Work autism spectrum disorder awake axonopathy biophysical properties cell type density dravet syndrome experience experimental study gene therapy genetic disorder diagnosis in vivo in vivo imaging infancy innovation mouse model neuronal cell body novel pre-clinical precision medicine response spatiotemporal synaptic failure targeted treatment transmission process two-photon voltage voltage clamp

项目摘要

PROJECT SUMMARY Dravet syndrome is a severe neurodevelopmental disorder that affects 1 in 16,000 children and is defined by treatment-resistant epilepsy, developmental delay, intellectual disability, autism spectrum disorder, and a high rate of sudden death. Dravet syndrome is caused by mutation in the gene SCN1A, which encodes the sodium (Na+) channel Nav1.1 How SCN1A mutation leads to the clinical entity known as Dravet syndrome remains unclear; this gap in knowledge has profoundly limited the practical impact that such a diagnosis has on treatment, quality of life, and long-term outcome for patients with this disorder. Prior work in experimental animal models of Dravet syndrome including Scn1a+/- mice suggests that loss of Nav1.1 leads to epilepsy via dysfunction of GABAergic inhibitory interneurons in the cerebral cortex, with the most prominent identified abnormalities being impaired action potential generation in a critical subtype of interneuron known as the parvalbumin-positive fast-spiking interneuron (PV-IN). However, data presented here indicates that, surprisingly, PV-IN dysfunction is transient, being restricted to a brief time window in early development, with subsequent recovery of high frequency firing. Preliminary data suggests that the specific locus of pathology in Dravet syndrome is actually PV-IN axons, with abnormal action potential propagation leading to conduction delay and synaptic failure, even though PV-INs have recovered the ability to generate action potentials at high frequency. This finding has important implications for the development of novel treatment approaches for Dravet syndrome, such as cell transplantation, gene therapy, or precision medicine. This new 5-year application from the lab of an early stage investigator uses innovative neuroscience approaches to test this new hypothesis as to the mechanism of pathology in Dravet syndrome. Proposed experiments will establish the molecular identity and physiological properties of Na+ channels in PV-IN axons in Scn1a+/- mice as compared to wild-type controls using targeted recordings from interneuron axons and detailed immunohistochemistry of axonal Na+ channels (Aim 1); determine the impact of PV-IN axonal dysfunction on the timing of feedforward inhibition in cerebral cortical circuits (Aim 2); and assess the activity of defined subsets of neurons in awake, behaving Scn1a+/- mice using in vivo imaging and electrophysiology to corroborate in vitro findings (Aim 3). The overall outcome of the proposed experiments will set forth a unifying hypothesis as to the pathophysiology of Dravet syndrome. Such knowledge is critical to the development of novel, targeted therapies for this currently incurable and untreatable disease. The long-term objective of this line of research is to apply preclinical data from experimental model systems to the development of new, mechanistically oriented therapies in human patients.

项目总结