Astrocyte exocytosis and its impact on synaptic transmission and plasticity.

描述（由申请人提供）：大脑含有神经胶质细胞，其数量是神经元的十倍。长期以来一直被认为只起被动作用，现在越来越多的证据表明，专门的胶质细胞，称为星形胶质细胞，通过与神经元的相互作用积极参与正常的脑功能。此外，星形胶质细胞-神经元相互作用参与癫痫发作活动。这一点很重要，因为引起癫痫的机制尚不清楚;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善疾病治疗的唯一合理方法。这一进展受到以下事实的阻碍，即星形胶质细胞-神经元相互作用的许多基本和重要方面仍然不清楚或未经实验探索。在这个提议中，我们试图确定星形胶质细胞是否具有细胞内钙兴奋性代码，以及这如何影响对附近神经元的突触反应。我们将测试的假设，动力学不同的细胞内钙波形星形胶质细胞内触发不同形式的胞吐作用，并影响附近的神经元在可分离的和刻板的方式。这些实验的结果将建立星形胶质细胞-神经元通信的逻辑，以及这些脑细胞类型之间的信号基础。因此，我们将发现在癫痫中出错的机制。我们有三个具体目标，具体目标1。测试的假设，细胞内钙瞬变的生理模式之间的星形胶质细胞胞吐作用的模式进行选择。具体目标2。检验星形胶质细胞胞吐作用的不同模式以可分离的方式影响神经元的假设。具体目标3。检验星形胶质细胞胞吐作用影响突触强度的短期和长期变化的假设。我们将确定星形胶质细胞在细胞内钙瞬变期间是否经历胞吐作用，以及确定对神经元突触传递和可塑性的影响。在这样做的基础上，我们将建立了解星形胶质细胞的神经元网络中的积极作用，在体外模型的癫痫发作的具体影响。这一点很重要，因为引起癫痫发作的机制还不完全清楚，并且癫痫的临床管理需求尚未得到满足。

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.