Glial control of neuronal receptive ending morphology

描述（由申请人提供）：我们的长期目标是了解经验改变神经元接受端形状的机制。在神经系统中，细胞的形状是可塑的。神经元的接受末梢，如树突棘和感觉突，在结构上是由经验重塑的，细胞神经科学中一个新兴的假设是，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。接受结尾结构是如何获得和改变形状的还不是很清楚；然而，人们一直认为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多数方面。在这里，我们挑战了这一观点，认为与接受末梢相关的神经胶质细胞在决定接受末梢形状和功能方面起着重要作用，因此，与突触前信号一起。神经胶质细胞是人类大脑中最丰富的细胞类型，它在神经系统疾病中起着广泛的作用。然而，神经胶质细胞在神经系统中所扮演的角色在很大程度上仍然是一个谜。一些观察结果表明，神经胶质细胞可以影响神经元接受末梢的形状：它们在正确的时间出现在正确的位置，它们可以感知突触后环境，它们的形状与神经元接受末梢细胞的形状动态相关，一些神经胶质蛋白的突变影响接受末梢的形状。我们之前已经证明，秀丽隐杆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，允许以目前在脊椎动物环境中甚至在果蝇中不可能的方式进行神经胶质功能的体内研究。我们建议使用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，2)重塑如何影响神经元功能和动物行为。从长远来看，我们计划探索我们在秀丽隐杆线虫之外发现的途径的保护。全面了解赋予神经系统解剖学和行为可塑性的机制对于理解大脑至关重要。这样的理解最终将使我们能够解决人类疾病，包括学习障碍和自闭症，这些疾病可能是由突触功能和可塑性的改变引起的。

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.