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

本发现拨款申请的目标是促进一个研究项目，重点了解突触如何在中枢神经系统中形成、维持和重塑。突触是大脑中神经元交流的关键部位。它们是具有高度发达的分子机制的专门结构，使化学神经传递成为可能。“突触”一词曾经仅限于突触前和突触后的神经元终端，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，星形胶质细胞与突触的突触前和突触后神经元终端之间表现出动态的结构相互作用，而星形胶质细胞曾被认为只是一种胶状结构。神经胶质细胞主动调查其神经元微环境，并通过钙介导的神经活性物质的释放来调节突触特性，向神经元提供反馈。尽管我们知道神经胶质在大脑中的重要性，但对神经元和神经胶质之间的通讯的细胞和分子机制的理解是不完整的。在这一发现基金提案中，我们将解决树突棘形成、稳定性和重塑中星形细胞突触结构和信号机制方面的几个未解决的问题。首先，我们将利用转基因动物、电生理学、分子生物学和高分辨率共聚焦显微镜技术确定GABA早期传输如何控制星形细胞平铺。接下来，我们将探讨神经胶质钙信号在树突棘重构中的重要性。最后，我们将研究活动依赖性突触重塑过程中胶质神经元结构的相互作用。这个发现基金项目将为对理解大脑回路感兴趣的学生提供一个极好的概念和技术培训。据设想，这些学生产生的数据也将对神经胶质-神经元相互作用和控制兴奋性突触形成、活动和可塑性的机制产生新的见解。

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.