Timing of Neurotransmitter Release

描述（由申请人提供）：大脑功能依赖于神经元之间的信息传递，这些信息传递在结构和功能上被定义为突触的位置。由于越来越清楚的是，许多脑部疾病，包括神经发育障碍和神经退行性疾病的早期阶段，都与突触功能失调有关，因此人们在理解突触传递的详细机制方面付出了相当大的努力。突触传递由三个组成部分组成，包括突触前释放含有囊泡的神经递质，神经递质通过神经元之间的空间扩散，以及突触后神经元中产生反应的受体的激活。这些事件发生在毫秒的时间尺度上，每个组件的时间被严格控制，以确保精确和有效的信息传输。然而，传递也是高度动态的，在对自然刺激模式的反应中表现出多种类型的可塑性。该项目的总体目标是确定活动如何控制突触前末端神经递质释放的同步，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发射器释放同步性的条件和机制。我们随后将在神经输出和突触后Ca2+信号方面测试活动依赖的异步递质释放的生理后果。这些研究将在小鼠的脑切片上进行，使用电压和电流钳记录以及钙成像和药理学操作。我们将使用小脑突触，因为它已经确定突触传递的精确时间对运动控制和运动学习等行为至关重要。这些研究的结果将提供一个重要的突触前机制来调节突触传递，可能在整个中枢神经系统的神经定时中起作用。

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.