Presynaptic regulation of neurotransmitter release in mammalian neuronal circuits

神经元回路的信息编码的多样性受神经元回路的幅度和频率的调节。 通过电压门控Ca 2+通道（CaV）的Ca 2+进入的位置。在哺乳动物的中枢 在神经系统中，CaV2.1通道是CNS功能的关键亚型，因为它是最重要的 有效的CaV2亚型触发突触囊泡（SV）释放。在大多数突触上， CaV2.1存在于较高水平且最接近SV。在突触发育过程中 由于CaV2.2的选择性减少，变得越来越依赖于CaV2.1， CaV2.3。以快速和时间精确的动作电位发出信号的神经元使用Cav2.1 具有快速SV释放动力学的排他性突触。此外，CaV2.1是主要的CaV2 与人CaV 2通道病相关的亚型，其在偏头痛、癫痫和 共济失调与这些发现相一致，SV释放的失调是这些和几个原因。 其他神经系统疾病。 尽管CaV2.1在中枢神经系统功能中的重要性，但我们对其分子机制知之甚少 调节突触上CaV2.1的功能。赫尔德的花萼，一种新的 听觉脑干中的突触前末梢利用快速和时间精确的动作电位 用于编码信息的信令。花萼经历了一个发展变化， 多个CaV2亚型仅限于CaV2.1。因为它是驱动突触后的唯一输入， 动作电位尖峰和由于直接测量突触前Ca2+电流的能力， 将它们与SV释放速率相关联，花萼是获得机制的例外模型。 深入了解SV释放和神经元回路输出的突触前调节。我们将使用 转基因小鼠模型和新的病毒载体，以操纵CaV2亚型在花萼， 不同的发展阶段。通过这些工具和拟议的实验，我们将确定 CaV2 α1亚基如何调节CaV2亚型水平、组织和与SV的接近性， 控制突触传递和神经元回路输出。鉴于CaV2的重要性， 调节突触传递的通道，以及 异常SV释放，我们设想我们的研究结果将提供基本的见解，如何 信息是由神经系统编码的，促进了治疗的发展。 广泛的神经和神经精神疾病。

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.