In-vivo and In-vitro Control of Adult Neural Progenitor Differentiation in the Hippocampus by Retinoic Acid. (360G-Wellcome-081633_Z_06_Z)

All-trans retinoic acid (tRA) has been widely investigated as a regulator of the embryonic CNS [1], a topic we have extensively studied [2-10]. Much less is known however regarding its influence on the adult brain [11]. We were the first to show that RA influences one aspect of hippocampal neuroplasticity neurogenesis [12, 13] and this proposal tests a new hypothesis that a precise equilibrium of tRA is essential to maintain this process. We will test this hypothesis by disrupting the bal ance of RA either by over-stimulation via treatment with 13-cis RA, used in the anti-acne drug Accutane [14] or under-stimulation using a retinol-binding protein null mutant mouse as a model for vitamin A deficiency. The effects of imbalance will be tested on three defined, quantifiable aspects of neurogenesis, determining: 1) the influence of varying RA concentrations on neuronal birth, 2) candidate cell cycle proteins influenced by RA and 3) RA s influence on neuronal maturation. New modulat ors of neurogenesis are currently sought because of their potential importance in CNS repair and psychiatric disease [15-17] and this proposal will characterize a new neurogenic modulator unique because of its ability to be adjusted by both dietary and genetic means.