The goal of this proposal is to identify candidate genes controlling neuroplasticity (CPGs) in visual cortex. Dark rearing slows the entire time course of the visual cortical critical period and therefore provides a means to dissociate changes associated with the state of plasticity from changes associated with maturation. A' differential display PCR screening, by this laboratory, of all of the expressed genes in the visual cortex of normal and dark reared cats at 5 and 20 weeks identified 23 CPGs. CPGs fall into 2 classes: """"""""plasticity""""""""' genes whose expression is enhanced in age/rearing conditions where neuroplasticity is maximal, and """"""""anti- plasticity"""""""" genes whose expression is opposite. One novel CPG that was identified is Mund3-3 (""""""""anti- plasticity""""""""), which plays an essential role in vesicle release at glutamatergic synapses. A novel """"""""plasticity"""""""" CPG is disabled-1 (Dab-1), a gene that plays a central role in the migration of cortical neurons. The project will address the following specific aims: 1. To test the hypothesis that CPG gene mutation will alter the time course of the physiologically defined critical period in mouse visual cortex. Electrophysiological and immediate early gene expression methodologies will determine the effect of Mund3-3 and Dab-1 mutation on susceptibility to monocular deprivation. 2. To test the hypothesis that """"""""plasticity"""""""" and """"""""anti-plasticity"""""""" CPGs will show distinct temporal associations with known laminar specific developmental events during the critical period in visual cortex. In situ hybridization and immunohistochemistry will be used to compare """"""""plasticity"""""""" and """"""""anti-plasticity"""""""" gene/protein expression in layer IV and extragranular visual cortical layers as a function of age and dark rearing. 3. To verify the identity of previously unsuspected CPGs indicated by the gene screen. Our screen has implicated novel CPGs with documented neurological functions. In addition to Mund3-3 and Dab-1, Plasticity Related Gene 1 (PRG-1) which influences axonal outgrowth, and two genes associated with Ras mediated cytoskeletal reorganization (Chimaerinl and Abl interacting protein 2) are tentatively identified. The identification of effector genes which control the visual cortical critical period would be a major step in unraveling molecular mechanisms of neuronal plasticity. Such information is essential to understanding processes such as neuronal development, regeneration, learning and memory and would further open the possibility of manipulation of nervous system neuroplasticity for therapeutic benefit.
