Timing of Neurotransmitter Release

描述（由申请人提供）：脑功能依赖于神经元之间在结构和功能上定义的称为突触的部位的信息传递。相当大的努力是针对了解突触传递的详细机制，因为它是越来越清楚，许多疾病的大脑，包括神经发育障碍和神经退行性疾病的早期阶段，与突触功能失调。突触传递由三个部分组成，包括含有囊泡的神经递质的突触前释放、神经递质通过神经元之间的空间的扩散以及在突触后神经元中产生响应的受体的激活。这些事件发生在毫秒级的时间尺度上，每个组件的时间都受到严格控制，以确保精确和有效的信息传输。然而，传输也是高度动态的，在对自然刺激模式的反应中显示出许多类型的可塑性。这个项目的总体目标是确定活动如何控制突触前末梢神经递质释放的同步性，以及这种活动依赖的可塑性如何有助于通过突触传递信息的时间。我们将首先建立控制递质释放同步性的条件和机制。随后，我们将测试活动依赖的异步发射器释放的神经输出和突触后Ca2+信号的生理后果。这些研究将使用电压和电流钳记录以及钙成像和药理学操作在小鼠脑切片中进行。我们将使用一个小脑突触，它是公认的，精确的时间突触传输是至关重要的行为，如运动控制和运动学习。这些研究的结果将提供一个重要的突触前机制，调节突触传递，可能在整个中枢神经系统的神经计时发挥作用的洞察力。

DESCRIPTION (provided by applicant): Brain function relies on information transfer between neurons at structurally and functionally defined sites called synapses. Considerable effort is directed at understanding the detailed mechanisms underlying synaptic transmission because it is increasingly clear that many diseases of the brain, including neurodevelopmental disorders and the earliest stages of neurodegenerative diseases, are associated with dysregulation of synaptic function. Synaptic transmission is composed of three components including the presynaptic release of neurotransmitter containing vesicles, diffusion of neurotransmitter through the space between neurons, and the activation of receptors that generate a response in the postsynaptic neuron. These events take place on a millisecond time scale, and the timing of each component is tightly controlled to ensure precise and efficient information transfer. Yet transmission is also highly dynamic, showing many types of plasticity in response to natural stimulus patterns. The overall goal of this project is to determine how activity controls the synchrony of neurotransmitter release from the presynaptic terminal, and how this activity-dependent plasticity contributes to the timing of information transfer through the synapse. We will first establish the conditions and mechanisms that control the synchronicity of transmitter release. We will subsequently test physiological consequences of activity dependent asynchronous transmitter release in terms of neural output and postsynaptic Ca2+ signaling. These studies will be conducted in brain slices from mice using voltage and current clamp recordings as well as calcium imaging and pharmacological manipulations. We will use a cerebellar synapse where it is well established that precise timing of synaptic transmission is critical for behaviors such as motor control and motor learning. The results from these studies will provide insight into an important presynaptic mechanism for regulating synaptic transmission that likely plays a role in neural timing throughout the CNS.