Cellular and Molecular Mechanisms Underlying Trophic Factor-Mediated Inhibitory Synapse Formation

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All animal behaviors - ranging from simple reflexes to complex motor patterns, and learning and memory rely critically upon precise connectivity patterns that are established during early development. Perturbation of this synaptic connectivity either due to genetical or environmental factors renders the nervous system dysfunctional and results in brain disorders such as the Autism spectrum or Alzheimer's diseases. Trophic molecules present in the extracellular milieu regulate many important aspects of brain cell connectivity. The precise cellular and molecular mechanisms by which trophic factors regulate the connectivity patterns between tens of billions of neurons remain, however poorly defined, due partially to the complex neuronal network formation in the mammalian brain. I will thus use a simpler model system, the fresh water pond snail, Lymnaea stagnalis where the formation of connectivity between functionally defined single pre- and postsynaptic neurons can be studied. In contrast to the well known action of trophic factors in excitatory connectivity formation, virtually nothing is known about inhibitory synapse formation. This information is particularly important because disturbance of inhibitory synapse formation or their perturbations result in an imbalance between excitation and inhibition, and hence have been linked to brain disorders such as autism spectrum, epilepsy and schizophrenia etc. In this study, I will thus focus on the role of trophic factors in inhibitory synapse formation by taking advantage of the in vitro reconstructed connectivity between single pre- and postsynaptic Lymnaea neurons, coupled with several state-of the-art neuroscience techniques such as the neuron silicon chip, electrophysiological, pharmacological, confocal microscopy and RNAi techniques. The knowledge gained from this study will help our efforts in repairing brain damage after stroke, injury and in treating neurodegenerative diseases. It will also help us develop further the chip technology in Canada and facilitate its commercialization.