Astrocyte exocytosis and its impact on synaptic transmission and plasticity.

描述(申请人提供)：大脑含有神经胶质细胞，其数量是神经元的十倍。长期以来，人们一直认为这只是一种被动的作用，现在越来越多的证据表明，被称为星形胶质细胞的特殊胶质细胞通过与神经元的相互作用积极参与正常的大脑功能。此外，星形胶质细胞-神经元的相互作用也参与了癫痫发作活动。这一点很重要，因为人们不了解导致癫痫的机制；尽管北美有300万癫痫患者，对他们来说，更好地了解所涉及的机制是提供改进疾病治疗的唯一合理途径。星形胶质细胞-神经元相互作用的许多基本和重要方面仍然不清楚或实验未被探索，这一事实阻碍了这一进展。在这项建议中，我们试图确定星形胶质细胞是否有细胞内钙兴奋性代码，以及这如何影响附近神经元的突触反应。我们将验证这一假设，即星形胶质细胞内动态不同的细胞内钙波形会触发不同形式的胞吐，并以可分离和固定的方式影响附近的神经元。综上所述，这些实验的结果将建立星形胶质细胞-神经元交流的逻辑，以及这些脑细胞类型之间信号传递的基础。因此，我们将发现癫痫出问题的机制。我们有三个特定的目标，特定的目标1.检验细胞内钙瞬变的生理模式在星形胶质细胞胞吐模式之间选择的假设。特定目的2.检验星形胶质细胞胞吐的不同模式以可分离的方式影响神经元的假设。具体目的3.检验星形胶质细胞胞吐作用影响突触强度短期和长期变化的假设。公共卫生相关性我们将确定星形胶质细胞在细胞内钙瞬变过程中是否经历胞吐作用，以及对神经元突触传递和可塑性的影响。在这样做的过程中，我们将为理解星形胶质细胞在神经元网络中的活跃作用奠定基础，并对癫痫发作的体外模型产生特殊的影响。这一点很重要，因为引起癫痫发作的机制还不完全清楚，临床治疗癫痫的需要还没有得到满足。

DESCRIPTION (provided by applicant): The brain contains glial cells, which out number neurons by ten-fold. Long considered to provide only a passive role, increasing evidence now suggests that specialized glial cells, called astrocytes, actively participate in normal brain function through interactions with neurons1. Moreover, astrocyte-neuron interactions are involved in epileptic seizure activity. This is of importance because the mechanisms that give rise to epilepsy are not understood; despite the fact that there are three million epilepsy patients in North America for whom a greater understanding of the mechanisms involved is the only rational way to provide improved disease treatment. Such progress is hampered by the fact that many fundamental and important aspects of astrocyte-neuron interactions remain unclear or experimentally unexplored. In this proposal we seek to determine if astrocytes have an intracellular calcium excitability code, and how this impacts synaptic responses to nearby neurons. We will test the hypothesis that kinetically distinct intracellular calcium waveforms within astrocytes trigger distinct forms of exocytosis, and affect nearby neurons in separable and stereotyped ways. Taken together the results of these experiments will establish the logic of astrocyte-neuron communication, and the basis of signaling between these brain cell types. We will thus discover the mechanisms that go awry in epilepsy. We have three specific aims, Specific Aim 1. Tests the hypothesis that physiological patterns of intracellular calcium transients select between modes of astrocyte exocytosis. Specific Aim 2. Tests the hypothesis that distinct modes of astrocyte exocytosis impact neurons in separable ways. Specific Aim 3. Tests the hypothesis that astrocyte exocytosis affects short and long term changes in synaptic strength. PUBLIC HEALTH RELEVANCE We will determine whether astrocytes undergo exocytosis during intracellular calcium transients, as well as determine the effects on neuronal synaptic transmission and plasticity. In so doing we will establish the basis for understanding the active roles of astrocytes within neuronal networks in general, with specific implications for in vitro models of epileptic seizures. This is important because the mechanisms that give rise to epileptic seizures are incompletely understood, and there is an unmet need for the clinical management of epilepsy.