Glial control of neuronal receptive ending morphology

描述(申请人提供)：我们的长期目标是了解经验改变神经元感受性终末形状的机制。在神经系统中，细胞的形状是可塑性的。神经元的感受性末梢，如树突和感觉突起，是由经验在结构上重塑的，细胞神经科学中的一个新兴假说是，这些形状的变化适应并定义了神经元输出的变化。因此，接受端结构的改变可能是神经系统可塑性的基础，并可能有助于包括学习和记忆在内的复杂认知能力。接受-结束结构如何获得和改变形状还不是很清楚；然而，已经假设突触后神经元对突触前活动的直接反应解释了这一现象的大部分方面。在这里，我们对这一观点提出质疑，认为与接受结束相关的胶质细胞在决定接受结束的形状中发挥着重要作用，因此与突触前线索一起发挥作用。胶质细胞是人脑中含量最丰富的细胞类型，神经胶质细胞广泛参与神经系统疾病。然而，神经胶质细胞在神经系统中扮演的角色在很大程度上仍然是个谜。一些观察表明，神经胶质细胞可以影响神经元感受性终末的形状：它们在正确的时间出现在正确的位置，它们可以感觉到突触后环境，它们的形状与神经元感受性终末细胞的形状动态相关，一些胶质蛋白的突变会影响接受性终末的形状。我们之前证明了线虫为探索神经系统中的神经胶质功能提供了一个独特的舞台，使得在体内研究神经胶质功能的方式目前在脊椎动物环境中甚至在果蝇中是不可能的。我们建议使用线虫强大的遗传分析方法来揭示1)神经胶质细胞影响神经元形状的分子机制，以及2)重塑如何影响神经元功能和动物行为。从长远来看，我们计划探索保护我们发现的线虫以外的路径。全面了解赋予神经系统解剖和行为可塑性的机制，对于理解大脑至关重要。这样的理解最终应该允许我们解决人类的障碍，包括学习障碍和自闭症，这些可能是由于突触功能和可塑性的改变而引起的。

DESCRIPTION (provided by applicant): Our long-term aim is to understand the mechanism by which neuronal receptive-ending shape is altered by experience. In the nervous system, cell shape is malleable. Neuronal receptive endings, such as dendritic spines and sensory protrusions, are structurally remodelled by experience, and an emerging hypothesis in cellular neuroscience is that these shape changes accommodate and define changes in neuron output. Alterations in receptive-ending structures may, therefore, underlie nervous system plasticity, and may contribute to complex cognitive capacities including learning and memory. How receptive-ending structures acquire and change shape is not well understood; however, it has been assumed that a direct response of postsynaptic neurons to presynaptic activity accounts for most aspects of the phenomenon. Here we challenge this view, suggesting that glial cells associated with receptive endings play major roles in determining receptive-ending shape, and therefore function, together with presynaptic cues. Glia are the most abundant cell type in the human brain, and glia contribute extensively to nervous system disease. However, the roles played by glia in the nervous system remain largely mysterious. Several observations suggest that glia could influence the shapes of neuronal receptive-endings: they are in the right place at the right time, they can sense the postsynaptic milieu, their shapes correlate dynamically with neuronal receptive-ending cell shapes, and mutations in some glial proteins affect receptive ending shape. We previously demonstrated that the nematode C. elegans offers a unique arena in which to explore glial functions in the nervous system, allowing in vivo studies of glial function to be adresed in ways curently not posible in vertebrate settings or even in Drosophila. We propose to use the powerful methods of genetic analysis in C. elegans to uncover 1) the molecular mechanisms by which glia affect neuronal shape, and 2) how remodeling afects neurons function and animal behavior. In the longer term, we plan to explore conservation of the pathways we identify beyond C. elegans. Achieving a comprehensive understanding of the mechanisms that endow nervous systems with anatomic and behavioural plasticity is of paramount importance in understanding the brain. Such an understanding should, eventually, allow us to tackle human disorders, including learning disabilities and autism, which may result from alterations in synaptic function and plasticity.