Neuronal-glia mechanisms in excitatory synapse formation, maintenance and plasticity

这项发现补助金申请的目的是促进一项研究计划，重点是了解突触是如何形成，维持和重塑中枢神经系统。突触是大脑中神经元通讯的关键部位。它们是具有高度发达的分子机制的专门结构，能够实现化学神经传递。术语突触曾经仅限于突触前和突触后神经元末梢，但现在我们知道非神经元细胞，特别是星形胶质细胞，也在突触发生，突触传递和可塑性中发挥作用。最近的研究表明，星形胶质细胞，曾经被认为是唯一的胶水样结构，显示动态的结构相互作用与突触前和突触后的神经元末梢的突触。神经胶质细胞主动地观察它们的神经元微环境，并通过钙介导的调节突触性质的神经活性物质的释放向神经元提供反馈。尽管神经胶质细胞在大脑中的重要性的知识，理解神经元和神经胶质细胞之间的通信的细胞和分子机制是不完整的。在这个发现补助金的建议，我们将解决几个悬而未决的问题，就星形胶质细胞突触的结构和信号机制，树突棘的形成，稳定性和重塑。首先，我们将使用转基因动物，电生理学，分子生物学和高分辨率共聚焦显微镜技术来确定早期GABA传输如何控制星形胶质细胞平铺。接下来我们将研究神经胶质细胞钙信号在树突棘重塑中的重要性。最后，我们将研究神经胶质细胞在活动依赖性突触重塑过程中的结构相互作用。这个发现资助项目将为有兴趣了解大脑回路的学生提供一个很好的概念和技术培训。据设想，这些学生产生的数据也将创造新的见解神经胶质-神经元的相互作用和机制，控制兴奋性突触的形成，活动和可塑性。

The goal of this Discovery Grant Application is to promote a research program focused on understanding how synapses are formed maintained and remodelled in the CNS. Synapses are key sites of neuronal communication in the brain. They are specialized structures with highly developed molecular machinery which enables chemical neurotransmission. The term synapse was once restricted to pre and postsynaptic neuronal terminals but now we know that non-neuronal cells, in particular astrocytes, also play a role in synaptogenesis, synaptic transmission and plasticity. Recent studies have revealed that astrocytes, once thought to act only as a glue-like structure, show dynamic structural interplay with pre and postsynaptic neuronal terminal of the synapse. The glial cells actively survey their neuronal microenvironment and give feedback to neurons through calcium mediated release of neuroactive substances that regulate synaptic properties. Despite the knowledge of the importance of glia in the brain the understanding of the cellular and molecular mechanisms that underlie communication between neurons and glia is incomplete. In this Discovery Grant proposal we will address several unresolved issues with respect to astrocyte-synapse structural and signalling mechanism in dendritic spine formation, stability and remodelling. First we will determine how early GABA transmission controls astrocytic tiling using transgenic animals, electrophysiology, molecular biology and high resolution confocal microscopy techniques. Next we will investigate the importance of glial calcium signalling in dendritic spine-remodelling. Finally we will investigate glial neuronal structural interplay during activity-dependent synaptic remodelling. This Discovery Grant project will provide an excellent conceptual and technical training for students interested in understanding brain circuitry. It is envisaged that data produced by these students will also create novel insights into glial-neuronal interactions and mechanisms that control excitatory synapse formation, activity and plasticity.