Candidate Genes Controlling Cortical Neuroplasticity

University Of Louisville Research Foundation Inc, Louisville KY

Investigators

Abstract

The aim of the proposal is to identify candidate genes that control neuronal plasticity during postnatal critical periods in neocortex. The proposed studies will utilize the most understood model of neuronal plasticity, the postnatal critical period in visual cortex. To date, studies aimed at identifying molecular mechanisms of visual cortical plasticity have concentrated on the signaling pathways from the cell surface to the nucleus. Dr. Mower's studies will extend this analysis to the output of transcriptional processes in the nucleus, the changes in gene expression which produce the long term structural and functional changes that underlie neuronal plasticity. The strategy capitalizes on the well- established finding that rearing animals in total darkness slows the entire time course of the critical period and prolongs neuronal plasticity far beyond its normal age limits. Prior electrophysiological results in Dr. Mower's laboratory indicate that the effect of dark rearing is to slow the entire time course of the critical period, such that at young ages normal animals are more plastic than dark reared, while at later ages dark reared animals are more plastic. Thus, a stringent criterion is that genes that are important for plasticity in visual cortex will show differences in expression between normal and dark reared animals that are of opposite direction in young vs. older animals. In preliminary work, Dr. Mower's laboratory has completed a differential display PCR (ddPCR) screening of all of the expressed genes in the visual cortex of normal and dark reared animals to directly identify candidate plasticity genes (CPGs) which are differentially expressed according to the above criterion. A manageable number (20) of CPGs were identified. These CPGs will be confirmed by northern blots of visual and frontal cortex from normal and dark reared animals, cloned and sequenced to determine homology to known genes, and analyzed at a cellular level by in-situ hybridization studies. Future uses of the candidate plasticity genes will include experiments to block their expression and determine effects on cortical plasticity in-vivo and in-vitro. The application of differential screening techniques is a novel experimental approach to analyzing critical period plasticity. The identification of effector genes that control development and plasticity would be a major leap in the state of knowledge regarding molecular mechanisms of the visual cortical critical period and neuronal plasticity. Such information is essential to our understanding of processes such as brain development, learning, and memory.