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:
  • 金额:
    $ 44.29万
  • 依托单位:
  • 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

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

项目成果

期刊论文数量(0)
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会议论文数量(0)
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ETHAN M GOLDBERG其他文献

ETHAN M GOLDBERG的其他文献

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{{ truncateString('ETHAN M GOLDBERG', 18)}}的其他基金

Assessing mechanisms of brain malformation in SCN3A encephalopathy using stem cell-based models
使用干细胞模型评估 SCN3A 脑病的脑畸形机制
  • 批准号:
    10841993
  • 财政年份:
    2023
  • 资助金额:
    $ 44.29万
  • 项目类别:
Mechanistically-oriented therapy for a progressive myoclonus epilepsy
进行性肌阵挛癫痫的机械导向治疗
  • 批准号:
    10444009
  • 财政年份:
    2022
  • 资助金额:
    $ 44.29万
  • 项目类别:
Mechanistically-oriented therapy for a progressive myoclonus epilepsy
进行性肌阵挛癫痫的机械导向治疗
  • 批准号:
    10591528
  • 财政年份:
    2022
  • 资助金额:
    $ 44.29万
  • 项目类别:
Pathomechanisms of SCN3A-related neurodevelopmental disorder
SCN3A相关神经发育障碍的发病机制
  • 批准号:
    10308091
  • 财政年份:
    2020
  • 资助金额:
    $ 44.29万
  • 项目类别:
Pathomechanisms of SCN3A-related neurodevelopmental disorder
SCN3A相关神经发育障碍的发病机制
  • 批准号:
    10544490
  • 财政年份:
    2020
  • 资助金额:
    $ 44.29万
  • 项目类别:
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
  • 批准号:
    10372046
  • 财政年份:
    2019
  • 资助金额:
    $ 44.29万
  • 项目类别:
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
  • 批准号:
    10599315
  • 财政年份:
    2019
  • 资助金额:
    $ 44.29万
  • 项目类别:
Dynamic two-photon calcium imaging and optogenetic manipulation of epileptic brain circuits in an experimental model of temporal lobe epilepsy
颞叶癫痫实验模型中癫痫脑回路的动态双光子钙成像和光遗传学操作
  • 批准号:
    9295077
  • 财政年份:
    2016
  • 资助金额:
    $ 44.29万
  • 项目类别:
K+ channels in fast-spiking cell synaptic transmission
快速尖峰细胞突触传递中的 K 通道
  • 批准号:
    7174626
  • 财政年份:
    2004
  • 资助金额:
    $ 44.29万
  • 项目类别:
K+ channels in fast-spiking cell synaptic transmission
快速尖峰细胞突触传递中的 K 通道
  • 批准号:
    6992656
  • 财政年份:
    2004
  • 资助金额:
    $ 44.29万
  • 项目类别:

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