Presynaptic regulation of neurotransmitter release in mammalian neuronal circuits

神经元回路编码信息的多样性受大小和 钙离子通过电压门控钙通道(Cav)进入的位置。在哺乳动物的中央 神经系统，CaV2.1通道是中枢神经系统功能的关键亚型，因为它是 在触发突触囊泡(SV)释放时有效的CaV2亚型。在大多数突触中， CaV2.1存在于较高水平，且最接近SVS。在突触发育过程中 由于选择性地减少Cav2.2和 CAV2.3。发出快速和时间精确动作电位信号的神经元使用Cav2.1 独有的突触具有快速的SV释放动力学。此外，CaV2.1是主要的CaV2 与人类CaV2通道病变相关的亚型，表现在偏头痛、癫痫和 共济失调。与这些发现一致的是，SV释放的失调是导致这些和几个 其他神经系统疾病。 尽管CaV2.1在中枢神经系统功能中占有重要地位，但我们对其分子机制知之甚少 在突触上调节这些CaV2.1的功能。谷氨酸能的Hold的花冠 听觉脑干中的突触前终末利用快速和时间上精确的动作电位 用于编码信息的信令。花萼经历了一个发育变化，从 多个CaV2子类型独占为CaV2.1。因为它是驱动突触后的唯一输入 动作电位峰值，并由于能够直接测量突触前钙电流和 将它们与SV释放率相关联，花萼是获得机械性能的特殊模型 对SV释放和神经元回路输出的突触前调节的洞察。我们将使用 转基因小鼠模型和新型病毒载体在花萼中操纵CaV2亚型 不同的发育阶段。有了这些工具和拟议的实验，我们将确定 CaV2α1亚基如何调节CaV2亚型水平、组织结构和与SVs的亲和性 控制突触传递和神经元回路输出。鉴于CaV2的重要性 通道在调节突触传递中的作用及其病理后果 异常的SV释放，我们预计我们的发现将提供基本的见解 信息由神经系统编码，促进了治疗方法的发展 广泛的神经和神经精神障碍。

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.