IGF-1 in neocortical development and plasticity

描述(由申请人提供)：了解树突生长的调节对于了解神经回路的形成和功能是必不可少的。树突是90%突触的靶点，树突分支的程度和模式对突触输入的整合起着至关重要的作用。伴随着许多发育障碍的认知障碍可能部分是由于对发育中的中枢神经系统中树突状细胞生长和可塑性的不适当调节造成的。目前的一个重大挑战是阐明控制树突在发育过程中详细阐述多少以及在哪里发挥作用的分子中介。 最近的证据表明，神经活动通过营养因子的作用影响树突状细胞的生长，营养因子主要促进新分支的形成和细化。然而，很可能有一个或多个因素更普遍地促进树突状细胞的细化，从而启动神经元对发育和可塑性的局部调节，这是由作用更受限的因素介导的。对于可能为树突状细胞的形成提供广泛但关键的刺激的药物，胰岛素样生长因子1(IGF-1)是特别令人感兴趣的。胰岛素样生长因子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大脑，也可以在脑血管细胞和脑内神经元和胶质细胞产生后以旁分泌和/或自分泌的方式发挥作用。几个实验室已经报道，IGF-1在体外促进神经元树突状细胞的形成。 此外，在IGF-1过度表达的转基因小鼠中，大脑皮层神经细胞的生长似乎增加，而在IGF-1活性降低的小鼠中，神经纤维的生长似乎减少。值得注意的是，人类研究和临床病例表明，发育过程中IGF-1信号的异常会导致智能损伤，部分原因可能是树突状细胞发育的失调。在这些研究的基础上，提出的实验将检验IGF-1调节神经细胞生长并为发育中的大脑皮层中的树突形成提供关键刺激这一假设的关键预测。依赖于IGF-1的树突发育调控将在体外使用发育中的大脑皮层的器官类型切片进行测试，也将在体内使用转基因小鼠进行测试，在转基因小鼠中，IGF-1信号在大脑中特定地增加或减少。

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.