Understanding how retinoic acid affects neurite outgrowth and synaptic function using invertebrate neurons.

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The main aim of my research program is to study the effects of the essential metabolite of Vitamin A, retinoic acid, on nervous system function. Retinoic acid is an important molecule for nervous system development and regeneration, as well as for learning and memory in the adult brain. We study these aspects of retinoid signaling in the central nervous system (CNS) of the invertebrate mollusc, Lymnaea stagnalis, which contains retinoids, retinoid receptors and retinoid metabolic enzymes. The retinoid receptors are nuclear receptors that generally act as ligand-activated transcription factors. However, it has now been well established, in both vertebrate and invertebrate CNS, that they can also exert important non-genomic effects during neurite outgrowth, and during synaptic plasticity, learning and memory. One of the main goals of my research program is to advance our knowledge and understanding of these non-genomic actions of retinoids. Unlike most vertebrate species, adult molluscan neurons can regenerate. Growth cones, located at the tips of growing neurites, guide these processes to their targets during axon pathfinding in development or regeneration. The growth cones of cultured regenerating motorneurons of the mollusc Lymnaea are large, robust and have been shown to respond with attractive turning responses to retinoids in a non-genomic manner. Over the next grant cycle, we will focus on the role of local protein synthesis in the growth cone responses to retinoids, with a focus on whether, and how, retinoid receptors are locally synthesized or trafficked, as well as the role of a specific microRNA, which can negatively regulate local protein synthesis during growth cone behaviour. We will also begin studying the axon pathfinding effects of retinoids in vivo. Another advantage of using molluscs to examine cellular effects of retinoids, is that many neurons located on the surface of the CNS are individually identifiable with known transmitters, synaptic partners and functions. We can culture and/or electrically record from single identified neurons involved in a specific behaviour, such as respiration or feeding. These behaviours can also be modified by training, and we have shown that retinoids and their receptors are important during memory formation. We have also determined that retinoids can rapidly modulate ion channels important for cell firing and neurotransmitter release. Over the next grant cycle, we will determine how retinoids affect ion channel activity and cell firing in a non-genomic manner, and whether this has direct effects on synaptic transmission. Our studies examining the effects of retinoids on synaptic changes and learning and memory, will range from analysis of single or synaptically paired cells in culture, to whole animal behaviour. These studies will highlight novel non-genomic actions of retinoic acid in the nervous system, during important processes such as neurite outgrowth and synaptic plasticity.