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，人们一直认为它只是一个被动的角色，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，积极参与正常的脑功能。此外，星形细胞-神经元的相互作用与癫痫发作活动有关。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更好的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尚未探索，这一事实阻碍了这种进展。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编码，以及这如何影响突触对附近神经元的反应。我们将测试星形胶质细胞内不同的动态细胞内钙波形触发不同形式的胞外分泌，并以可分离和刻板的方式影响附近神经元的假设。综合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信号传导的基础。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。验证了在星形胶质细胞胞吐模式之间，细胞内钙瞬态的生理模式选择的假设。具体目标2。验证星形胶质细胞胞吐的不同模式对神经元的影响是可分离的。具体目标3。验证星形胶质细胞胞吐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是否在细胞内钙瞬变期间发生胞吐，以及确定对神经元突触传递和可塑性的影响。通过这样做，我们将为理解星形胶质细胞在神经网络中的活跃作用奠定基础，并对癫痫发作的体外模型具有特殊意义。这一点很重要，因为引起癫痫发作的机制尚不完全清楚，对癫痫临床管理的需求尚未得到满足。

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.