IGF-1 in neocortical development and plasticity

描述（由申请人提供）：了解树突状细胞生长的调节对于了解神经回路的形成和功能至关重要。树突是90%的突触的靶点，树突分支的程度和模式都对突触输入的整合产生重要影响。伴随许多发育障碍的认知障碍可能部分是由于发育中的CNS中树突生长和可塑性的不适当调节。目前的一个重大挑战是阐明控制树突在发育过程中产生多少和在哪里的分子介质。 最近的证据表明，神经活动通过营养因子的作用影响树突的生长，这些营养因子集中地促进新分支的形成和发育。然而，很可能有一种或多种因素更普遍地促进树突的发育，从而使神经元对发育和可塑性的局灶性调节发挥作用，而这种调节是由具有更有限作用的因素介导的。关于可能为树突状细胞的发育提供广泛但关键的刺激的试剂，胰岛素样生长因子1（IGF-1）是特别感兴趣的。IGF受体在发育中的大脑中广泛表达。IGF-1可以作为内分泌因子从血浆进入脑，并且还可以在脑血管系统细胞和脑内的神经元和神经胶质细胞产生后以旁分泌和/或自分泌方式起作用。几个实验室已经报道，IGF-1在体外促进神经元树突的形成。 此外，在IGF-1过表达的转基因小鼠中，大脑皮层中神经元的生长似乎增加，而在IGF-1活性降低的小鼠中，大脑皮层中神经元的生长似乎减少。重要的是，人类研究和临床病例表明，发育期间异常的IGF-1信号传导可导致智力障碍，这可能部分源于树突发育的失调。在这些研究的基础上，提出的实验将测试IGF-1调节神经元生长的假设的关键预测，并为发育中的大脑皮层中的树突发育提供关键刺激。树突发育的IGF-1依赖性调节将在体外进行测试，使用发育中的大脑皮层的器官型切片，以及在体内，使用转基因小鼠，其中IGF-1信号在脑内特异性增加或减少。

DESCRIPTION (provided by applicant): Understanding the regulation of dendritic growth is essential to understanding how neural circuits form and function. Dendrites are the targets of 90% of all synapses, and both the extent and pattern of dendritic branching critically influence the integration of synaptic inputs. The cognitive impairments that accompany many developmental disorders are likely to result in part from inappropriate regulation of dendritic growth and plasticity in the developing CNS. One significant challenge currently is elucidating the molecular mediators that control of how much and where dendrites elaborate during development. Recent evidence suggests that neural activity influences dendritic growth through the actions of trophic factors, which focally promote formation and elaboration of new branches. It is likely, however, that one or more factors promote dendritic elaboration more generally and thereby prime neurons for the focal regulation of development and plasticity that is mediated by factors with more restricted actions. With respect to agents that might provide a broad but critical stimulus for dendritic elaboration, insulin-like growth factor 1 (IGF-1) is of particular interest. IGF receptors are widely expressed in the developing brain. IGF-1 can cross from the plasma into the brain as an endocrine factor, and also may act in a paracrine and/or autocrine fashion following production by cells of the cerebral vasculature and by neurons and glia within the brain. Several laboratories have reported that IGF-1 promotes dendritic elaboration by neurons in vitro. Moreover, the growth of neuropil in the cerebral cortex appears to be increased in transgenic mice in which IGF-1 is overexpressed and decreased in mice in which IGF-1 activity is decreased. Significantly, human studies and clinical cases indicate that abnormal IGF-1 signaling during development can result in intellectual impairment, which may arise in part from dysregulation of dendritic development. Building upon such studies, the experiments proposed will test key predictions of the hypothesis that IGF-1 modulates the growth of neuropil and provides a critical stimulus for dendritic elaboration in the developing cerebral cortex. IGF-1-dependent regulation of dendritic development will be tested in vitro, using organotypic slices of the developing cerebral cortex, and also in vivo, using transgenic mice in which IGF-1 signaling is increased or decreased specifically within the brain.