IGF-1 in neocortical development and plasticity

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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.