Transmitter-mediated interactions between neurons and astrocytes

描述（由申请人提供）：整个中枢神经系统的星形胶质细胞为其邻近神经元提供一系列服务，包括清除释放后的递质和提供代谢支持。人们最近才认识到星形胶质细胞不仅仅是照料者，而且还密切参与中枢神经系统的主要功能——处理信息。虽然星形胶质细胞的反应速度不能与神经元的速度相匹配，但它们可以通过隔离或打开相邻突触之间的通信通路来改变神经元之间的相互作用。此外，星形胶质细胞通过响应离子梯度的变化、释放神经递质和释放神经活性物质，与神经元进行双向交流。本研究的目的是确定星形胶质细胞通过星形细胞板足突的伸展和收缩改变突触与相邻突触隔离的能力和机制。这些目标将通过结合使用双光子显微镜来直接观察过程精细，电生理学来测量突触强度，受体活性的药理学操作，笼状谷氨酸的双光子光解来快速激活树突棘大小体积的受体，细胞内笼状钙的闪光光解，以及通常缺失的谷氨酸门控离子通道的表达来改变钙的内流。这些研究将揭示控制谷氨酸释放到细胞外空间的必要但潜在破坏性影响的策略。谷氨酸清除紊乱引起的兴奋性毒性损伤与多种神经系统疾病有关。此外，在精神分裂症和重度抑郁症患者中，神经胶质细胞数量低于正常水平，表明神经元营养支持减少，这可能导致神经元大小、树突棘密度和突触蛋白水平降低，以及在这些情况下fMRI观察到的异常。了解星形胶质细胞可塑性及其在突触功能中的作用，有望为管理精神疾病中传播异常提供独特的方法。

DESCRIPTION (provided by applicant): Astrocytes throughout the CNS provide an array of services for their neighboring neurons including removing transmitters following release and providing metabolic sustenance. The realization that astrocytes are not merely caretakers but are also intimately involved in the main purpose of the CNS, processing information, is recent. Although the responses of astrocytes cannot match the speed of neurons, they can alter the interactions between neurons by isolating or opening pathways of communication between adjacent synapses. Additionally, astrocytes communicate between themselves and, bi-directionally, with neurons by responding to alterations in ionic gradients, released neurotransmitters, and by releasing neuroactive substances. The aim of the present research is to determine the ability of, and mechanisms by which, astrocytes alter the isolation of synapses from neighboring synapses by the extension and retraction of astrocytic lamellipodial processes. These objectives will be addressed using a combination of 2 photon microscopy to directly observe process elaboration, electrophysiology to measure synaptic strength, pharmacological manipulation of receptor activity, 2 photon photolysis of caged glutamate to rapidly activate receptors in dendritic spine-sized volumes, flash photolysis of intracellular caged calcium, and expression of normally absence glutamate- gated ion channels to alter calcium influx. These studies will uncover strategies to control the necessary but potentially damaging effects of releasing glutamate into the extracellular space. Disruption of glutamate clearance followed by excitotoxic damage has been implicated in a variety of neurological pathologies. In addition, in schizophrenia and major depression, glial cell number is subnormal suggesting diminished trophic support of neurons that likely contributes to the reduced neuronal size, density of dendritic spines, and levels of synaptic proteins, as well as the abnormalities observed in fMRI in these conditions. Understanding astrocyte plasticity and its role in synaptic function promises unique approaches to managing the abnormalities in transmission in mental disease.