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
• 负责人: Samuel Matthew Young
• 金额: $ 38.54万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/10302979
• 关键词: Action Potentials; Alternative Splicing; Ataxia; Auditory; Brain Stem; Cells; Data; Development; Electron Microscopy; Electrophysiology (science); Epilepsy; Genetic Transcription; Glutamates; Goals; Human; Hybrids; Impairment; Kinetics; Knockout Mice; Knowledge; Location; Maps; Measures; Mediating; Migraine; Modeling; Molecular; Nervous System Physiology; Nervous system structure; Neuraxis; Neurons; Output; P-Q type voltage-dependent calcium channel; Pathologic; Presynaptic Terminals; Protein Isoforms; Proteins; Publishing; Regulation; Role; Signal Transduction; Spike Potential; Synapses; Synaptic Transmission; Synaptic Vesicles; Transgenic Mice; Variant; Viral Vector; conditional knockout; experimental study; gutless adenoviral vector; insight; models and simulation; mouse model; mutant; nervous system disorder; neuronal circuitry; neuropsychiatric disorder; neurotransmitter release; novel; patch clamp; postsynaptic; preference; presynaptic; protein protein interaction; therapy development; tool; trafficking; vesicular release; voltage

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.

神经元电路编码的信息多样性受大小和 Ca2+进入的位置，通过电压门控Ca2+通道（CAV）的位置。在哺乳动物中央 神经系统，CAV2.1通道是CNS功能的关键亚型，因为它是最多的 触发突触囊泡（SV）释放时有效的CAV2亚型。在大多数突触中， Cav2.1存在于更高级别，最接近SV。在开发突触期间 由于选择性减少Cav2.2和 cav2.3。用快速且暂时精确的动感电位发出信号的神经元使用CAV2.1 具有快速SV释放动力学的独家突触。另外，Cav2.1是主要的CAV2 与人类Cav2通道病相关的同工型，在偏头痛，癫痫和 共济失调。与这些发现一致，SV释放的失调是导致这些的原因，有几个 其他神经系统疾病。 尽管CAV2.1在CNS功能中的重要性，但我们对分子机制知之甚少 调节这些CAV2.1在突触中的功能。 hold的花萼，谷氨酸能 听觉脑干的突触前终端利用快速且暂时精确的动作电位 用于编码信息的信号。花萼经历了从拥有的发展 多个CAV2亚型至CAV2.1。因为这是驱动突触后驱动的唯一输入 动作电位尖峰，并且由于能够直接测量突触前Ca2+电流和 将它们与SV释放率相关 对SV释放和神经元电路输出的突触前调节的见解。我们将使用 转基因小鼠模型和新型病毒载体在花萼上操纵Cav2亚型的新型病毒载体。 不同的发展阶段。使用这些工具和建议的实验，我们将确定 CAV2α1亚基如何调节CAV2亚型水平，组织和靠近SVS 控制突触传递和神经元电路输出。考虑到Cav2的重要性 控制突触传播的渠道，以及 异常SV发布，我们设想我们的发现将提供有关如何 信息由神经系统编码，支持开发 广泛的神经和神经精神疾病。