Presynaptic regulation of neurotransmitter release in mammalian neuronal circuits

哺乳动物神经回路中神经递质释放的突触前调节

基本信息

  • 批准号:
    10524734
  • 负责人:
  • 金额:
    $ 37.01万
  • 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:
    2019-12-01 至 2024-11-30
  • 项目状态:
    已结题

项目摘要

The diversity of information encoding by neuronal circuits is regulated by the magnitude and location of Ca2+ entry though voltage-gated Ca2+ channels (CaV). In the mammalian central nervous system, the CaV2.1 channel is the critical subtype for CNS function since it is the most efficient CaV2 subtype at triggering synaptic vesicle (SV) release. At the majority of synapses, CaV2.1 is present at higher levels and in closest proximity to SVs. During development synapses become progressively more dependent on CaV2.1 due to selective reduction of CaV2.2 and CaV2.3. Neurons that signal with rapid and temporally precise action-potentials use Cav2.1 exclusive synapses that have fast SV release kinetics. Additionally, CaV2.1 is the dominant CaV2 isoform associated with human CaV2 channelopathies that manifest in migraine, epilepsy, and ataxia. Consistent with these findings, dysregulation of SV release is a cause of these and several other neurological disorders. Despite the importance of CaV2.1 in CNS function, we know little about the molecular mechanisms that regulate these CaV2.1 functions at the synapse. The calyx of Held, a glutamatergic presynaptic terminal in the auditory brainstem utilizes rapid and temporally precise action potential signaling for encoding information. The calyx undergoes a developmental change from having multiple CaV2 subtypes to CaV2.1 exclusively. Since it is the sole input to drive post-synaptic action potential spiking and due to the ability to directly measure presynaptic Ca2+ currents and correlate them to SV release rate, the calyx is an exceptional model for gaining mechanistic insights into the presynaptic regulation of SV release and neuronal circuit output. We will use transgenic mouse models and novel viral vectors to manipulate CaV2 subtypes at the calyx during different developmental stages. With these tools and proposed experiments, we will determine how the CaV2 α1 subunit regulates CaV2 subtype levels, organization and proximity to SVs thereby controlling synaptic transmission and neuronal circuit output. Given the importance of CaV2 channels in regulating synaptic transmission, as well as the pathological consequences of aberrant SV release, we envision that our findings will provide fundamental insights into how information is encoded by the nervous system, facilitating the development of treatments for a wide range of neurological and neuropsychiatric disorders.
神经元回路编码信息的多样性受信号的大小和大小的调控

项目成果

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Samuel Matthew Young其他文献

Samuel Matthew Young的其他文献

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{{ truncateString('Samuel Matthew Young', 18)}}的其他基金

Elucidating the roles of CACNA2D2 and CACNA2D3 in presynaptic regulation of mammalian synaptic function
阐明 CACNA2D2 和 CACNA2D3 在哺乳动物突触功能突触前调节中的作用
  • 批准号:
    10450212
  • 财政年份:
    2022
  • 资助金额:
    $ 37.01万
  • 项目类别:
Presynaptic regulation of neurotransmitter release in mammalian neuronal circuits
哺乳动物神经回路中神经递质释放的突触前调节
  • 批准号:
    10302979
  • 财政年份:
    2019
  • 资助金额:
    $ 37.01万
  • 项目类别:
Presynaptic regulation of neurotransmitter release in mammalian neuronal circuits
哺乳动物神经回路中神经递质释放的突触前调节
  • 批准号:
    10057401
  • 财政年份:
    2019
  • 资助金额:
    $ 37.01万
  • 项目类别:
Presynaptic regulation of neurotransmitter release in mammalian neuronal circuits
哺乳动物神经回路中神经递质释放的突触前调节
  • 批准号:
    9884425
  • 财政年份:
    2019
  • 资助金额:
    $ 37.01万
  • 项目类别:
Regulation of Synaptic Vesicle Dynamics in the Auditory System
听觉系统突触小泡动力学的调节
  • 批准号:
    9479765
  • 财政年份:
    2015
  • 资助金额:
    $ 37.01万
  • 项目类别:
Regulation of Synaptic Vesicle Dynamics in the Auditory System
听觉系统突触小泡动力学的调节
  • 批准号:
    10194445
  • 财政年份:
    2015
  • 资助金额:
    $ 37.01万
  • 项目类别:
Regulation of Synaptic Vesicle Dynamics in the Auditory System
听觉系统突触小泡动力学的调节
  • 批准号:
    10401920
  • 财政年份:
    2015
  • 资助金额:
    $ 37.01万
  • 项目类别:
Regulation of Synaptic Vesicle Dynamics in the Auditory System
听觉系统突触小泡动力学的调节
  • 批准号:
    10621329
  • 财政年份:
    2015
  • 资助金额:
    $ 37.01万
  • 项目类别:

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