Investigation on the regulation of synaptic transmission by glial molecules

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In this study, we aimed to elucidate the molecular mechanism of glia-neuron interaction, and to develop essential therapy for brain diseases based on the glial regulation of neural transmission. We achieved investigations on the following subjects ;1) Identification of an animal model for investigating glial contribution on neurodegenerationThe gracile axonal dystrophy mouse is pathologically characterized by presynaptic degeneration at axon terminals. The mouse is suitable for investigating the functional change of glial cells during loss of presynaptic structures We employed a positional cloning approach to identify the gene for the mutation. We found that a segment of ubiquitin C-terminal hydrolase L1 gene is deleted in the mutant.2) Development of a new therapy of retinal degeneration by modification of glial cell functionWe demonstrate a novel pathway of light-induced photoreceptor apoptosis involving the low-affinity neurotrophin receptor p75 (p75NTR). Retinal degeneration upregulated both p75NTR and the high-affinity neurotrophin receptor TrkC in different parts of Muller glial cells. Exogenous neurotrophin-3 (NT-3) increased, but nerve growth factor (NGF) decreased basic fibroblast growth factor (bFGF) production in Muller cells, which can directly rescue photoreceptor apoptosis. Blockade of p75NTR prevented bFGF reduction and resulted in both structural and functional photoreceptor survival in vivo.3) MiscellaneousWe found that PEPA is a novel allosteric modulator of AMPA type glutamate receptors. PEPA affects desensitization but not deactivation of the receptors. We generated mice lacking the function of glial glutamate transporter, GLAST.These findings are useful for further investigation of glial contribution on neural transmission.