Neuronal and Behavioral Deficits Associated with Scn2a Deficiency in Autism Spectrum Disorder

自闭症谱系障碍中与 Scn2a 缺乏相关的神经元和行为缺陷

基本信息

  • 批准号:
    10599103
  • 负责人:
  • 金额:
    $ 38.15万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-04-01 至 2026-03-31
  • 项目状态:
    未结题

项目摘要

Project Summary/Abstract Autism spectrum disorder (ASD) is a neurodevelopmental disorder associated with impaired social communications and behavioral abnormalities, which affects ~1 in 54 children in the United States (CDC.gov). SCN2A, encoding neuronal voltage-gated sodium channel Nav1.2, has been identified as one of the leading genes associated with ASD. We have characterized a novel Scn2a-deficient mouse model that is generated via targeted gene-trap knockout (gtKO) strategy and possesses a built-in genetic rescue element. Our preliminary data revealed profound behavioral abnormalities in homozygous Scn2agtKO/gtKO mice including anxiety-like behaviors, impaired nesting and social deficits. We also identified elevated excitation-inhibition (E/I) balance in pyramidal neurons of mPFC, which has been implicated in ASD and social deficits. However, a critical gap exists regarding how in vivo neuronal firings in mPFC are affected by elevated E/I balance and to what extent the manipulation of E/I balance will alter the behavioral outcomes in Scn2agtKO/gtKO mice. To address this gap, we propose to test an overarching hypothesis that Scn2a deficiency increases E/I balance, impairs neuronal responses in mPFC, and results in social deficits that can be rescued with targeted genetic and pharmacological interventions. In Aim 1, we will assess the synaptic properties and in vivo firing of neurons in mPFC using brain- slice patch-clamp recording and Neuropixels in vivo recording. Our findings are expected to provide cellular-level and local network level neuropathological mechanisms of Scn2a deficiency. In Aim 2, we will determine neuronal firings and behavioral outcomes in response to manipulating E/I balance in mPFC microcircuit using optogenetics and chemogenetics. Our findings will bolster the significance of E/I balance modulation for correction of behavioral deficits. In Aim 3, we will evaluate the efficacy of timed genetic and pharmacological rescue to determine optimal windows for intervention. Our study is significant in the following ways: i) SCN2A deficiency to be studied is among the leading monogenetic forms of ASD; ii) Excitation and inhibition (E/I) balance of mPFC microcircuit to be thoroughly dissected is closely associated with social deficits; and iii) Genetic rescue and pharmacological intervention to be tested are of clear clinical relevance, and will provide translational basis to inform therapeutic development for the treatment of Scn2a-deficiency related disorders. Our study has the following innovations: i) use of novel Scn2agtKO/gtKO mice that display profound cellular and behavioral deficits; ii) innovative ways to achieve genetic and pharmacological rescue; and iii) use of cutting-edge technologies including high density Neuropixels in vivo recordings. The applicant is an early stage investigator (ESI), whose team has extensive expertise in sodium channel electrophysiology, animal behaviors, genetics and pharmacology. The team is well suited to carry out the proposed work to its full completion within the project timeframe, and generate impactful outcomes to advance the field.
项目总结/摘要 自闭症谱系障碍(ASD)是一种神经发育障碍, 沟通和行为异常,影响美国54名儿童中的1名(CDC. gov)。 SCN 2A编码神经元电压门控钠通道Nav1.2,已被鉴定为主要的神经元电压门控钠通道之一。 与ASD相关的基因我们已经表征了一种新的Scn 2a缺陷小鼠模型,其通过以下途径产生: 靶向基因陷阱敲除(gtKO)策略,并具有内置的遗传拯救元件。我们的初步 数据显示纯合子Scn 2agtKO/gtKO小鼠存在严重的行为异常,包括焦虑样 行为,筑巢受损和社会缺陷。我们还确定了兴奋-抑制(E/I)平衡的升高, mPFC的锥体神经元,这与ASD和社会缺陷有关。然而, 关于体内mPFC中的神经元放电如何受到升高的E/I平衡的影响以及在多大程度上 E/I平衡的操纵将改变Scn 2agtKO/gtKO小鼠的行为结果。为了弥补这一差距,我们 我建议测试一个总体假设,即Scn 2a缺乏增加E/I平衡,损害神经元 mPFC的反应,并导致社会缺陷,可以用靶向遗传和药理学方法挽救 干预措施。在目标1中,我们将评估突触特性和使用脑- 切片膜片钳记录和神经元在体记录。我们的发现有望提供细胞水平的 和局部网络水平的神经病理学机制的Scn 2a缺陷。在目标2中,我们将确定神经元 使用光遗传学操纵mPFC微电路中的E/I平衡的放电和行为结果 和化学遗传学我们的研究结果将支持E/I平衡调节对纠正 行为缺陷在目标3中,我们将评估定时遗传和药物拯救的疗效, 确定干预的最佳窗口。我们的研究在以下方面具有重要意义:i)SCN 2A缺陷 待研究的是ASD的主要单基因形式之一; ii)mPFC的兴奋和抑制(E/I)平衡 要彻底解剖的微电路与社会缺陷密切相关;和iii)遗传拯救和 待测试的药理学干预具有明确的临床相关性,并将为 为Scn 2a缺乏相关疾病的治疗提供信息。我们的研究 以下创新:i)使用表现出严重的细胞和行为缺陷的新型Scn 2agtKO/gtKO小鼠; ii) 创新的方法来实现遗传和药物拯救;和三)使用尖端技术 包括高密度神经像素体内记录。申请人是早期研究者(ESI),其 团队在钠通道电生理学、动物行为学、遗传学和 药理学该小组非常适合在项目内完成拟议的工作 时间表,并产生有影响力的结果,以推动该领域的发展。

项目成果

期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
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Yang Yang其他文献

Automatic tagging by exploring tag information capability and correlation
通过探索标签信息能力和相关性来自动标记
  • DOI:
    10.1007/s11280-011-0132-6
  • 发表时间:
    2012-05
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Huang Zi;Shen Heng Tao;Yang Yang;Li Zhoujun
  • 通讯作者:
    Li Zhoujun
Photodegradation of Dechlorane Plus in n-nonane under the irradiation of xenon lamp
氙灯照射下正壬烷中 DeChlorane Plus 的光降解
Is Ignorance Bliss?
无知是福吗?
Structure-independent conductance of thiophene-based single-stacking junctions
  • DOI:
    10.1002/anie.201913344.
  • 发表时间:
    2020
  • 期刊:
  • 影响因子:
  • 作者:
    Li Xiaohui;Wu Qingqing;Bai Jie;Hou Songjun;Jiang Wenlin;Tang Chun;Song Hang;Huang Xiaojuan;Zheng Jueting;Yang Yang;Liu Junyang;Hu Yong;Shi Jia;Liu Zitong;Lambert Colin J.;Zhang Deqing;Hong Wenjing
  • 通讯作者:
    Hong Wenjing

Yang Yang的其他文献

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{{ truncateString('Yang Yang', 18)}}的其他基金

Mechanistic insights into multifaceted roles of coronavirus exoribonuclease complex
冠状病毒外核糖核酸酶复合物多方面作用的机制见解
  • 批准号:
    10713523
  • 财政年份:
    2023
  • 资助金额:
    $ 38.15万
  • 项目类别:
CK22-008, Building Mathematical Modeling Workforce Capacity to Support Infectious Disease and Healthcare Research - 2022
CK22-008,建立数学建模劳动力能力以支持传染病和医疗保健研究 - 2022
  • 批准号:
    10913951
  • 财政年份:
    2023
  • 资助金额:
    $ 38.15万
  • 项目类别:
Building Mathematical Modeling Workforce Capacity to Support Infectious Disease and Healthcare Research - 2022
建设数学建模劳动力能力以支持传染病和医疗保健研究 - 2022
  • 批准号:
    10861383
  • 财政年份:
    2023
  • 资助金额:
    $ 38.15万
  • 项目类别:
An Evolvable Metalloenzyme Platform for Stereoselective Radical Biocatalysis
用于立体选择性自由基生物催化的可进化金属酶平台
  • 批准号:
    10792280
  • 财政年份:
    2022
  • 资助金额:
    $ 38.15万
  • 项目类别:
An Evolvable Metalloenzyme Platform for Stereoselective Radical Biocatalysis
用于立体选择性自由基生物催化的可进化金属酶平台
  • 批准号:
    10502191
  • 财政年份:
    2022
  • 资助金额:
    $ 38.15万
  • 项目类别:
An Evolvable Metalloenzyme Platform for Stereoselective Radical Biocatalysis
用于立体选择性自由基生物催化的可进化金属酶平台
  • 批准号:
    10650814
  • 财政年份:
    2022
  • 资助金额:
    $ 38.15万
  • 项目类别:
Rapid 3D Ultrasound Tomography Reconstruction Methods for Guided Interventions
用于引导干预的快速 3D 超声断层扫描重建方法
  • 批准号:
    10670956
  • 财政年份:
    2022
  • 资助金额:
    $ 38.15万
  • 项目类别:
Rapid 3D Ultrasound Tomography Reconstruction Methods for Guided Interventions
用于引导干预的快速 3D 超声断层扫描重建方法
  • 批准号:
    10509562
  • 财政年份:
    2022
  • 资助金额:
    $ 38.15万
  • 项目类别:
Neuronal hyperexcitability and seizures in a Scn2a deficient mouse model
Scn2a 缺陷小鼠模型中的神经元过度兴奋和癫痫发作
  • 批准号:
    10445083
  • 财政年份:
    2021
  • 资助金额:
    $ 38.15万
  • 项目类别:
Neuronal and Behavioral Deficits Associated with Scn2a Deficiency in Autism Spectrum Disorder
自闭症谱系障碍中与 Scn2a 缺乏相关的神经元和行为缺陷
  • 批准号:
    10211758
  • 财政年份:
    2021
  • 资助金额:
    $ 38.15万
  • 项目类别:

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