DEVELOPMENT OF LOCAL CONNECTIONS IN CEREBRAL CORTEX

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During development, young neurons within the nervous system must form specific connections to both local and long distance targets. Within the cerebral cortex, the majority of synaptic connections are formed by locally-projecting neurons; thus it seems likely that the malformation of such connections will be implicated in the generation of at least some of the epilepsies of childhood. Indeed, use of high resolution MRI has made it increasingly apparent that a number of the epilepsies are caused b cortical malformations. We need to understand much more about the rules by which connections form in the normal cortex, in order to understand and possibly treat the defects within cortical malformations that lead to epilepsy. The rules by which local connections are established during development appear to employ highly specific mechanisms of laminar recognition. The major aim of this research proposal is to understand the processes by which young neurons in the mammalian neocortex form local (intrinsic) axonal connections with appropriate sets of target neurons in restricted sets of layers. We will explore the development of the local projections of neurons the cells of cortical layer 2/3, which form extensive interconnections within layer 2/3 and also project to the deep layers 5 and 6; those of neurons in layer 5, which projects up to layer 2/3 and to the deep layers; and finally those of the cortical layer 6, which sends a feedback projection to layer 4. The following specific aims are outlined: 1) We will use organotypic cultured slices of the developing visual cortex to ask whether local circuit formation be recapitulated in slices, and whether axons require activity to establish their layer-specific patterns of axon collaterals. 2) By placing neurons in ectopic laminar positions, we will ask whether the formation of local projections an active process that involves the specific recognition of layer-specific cues. 3) Using membrane stripe assays in which neurons of the different layers are presented with a choice of growth substrates, we will explore the nature of the molecular cues that direct local axonal growth and sprouting in the cortex.