In adult demyelinating diseases such as multiple sclerosis, new early stage myelin-producing cells proliferate but fail to rebuild the insulation around nerve fibers as they would during normal development. Myelin increases the speed and efficiency of nerve impulses, protects the nerve fiber from injury, and provides metabolic support to nerve fibers. The aim of this project is to determine how glutamate signaling between nerve fibers and early stage myelin-producing cells provides a signal that directs development of the myelin sheath. Beyond its potential to increase our basic understanding of normal myelination processes, the work also has the potential to increase our understanding of demyelinating diseases, such as multiple sclerosis. The PI will instruct, participate, and oversee all experiments outlined in the research proposal. In conjunction with the University of Alabama Center for Community Outreach Development (CORD), members of the DeSilva laboratory will give a one hour interactive lecture highlighting how myelin increases the speed of nerve impulses, and the emerging roles of glia in the central nervous system to designated 7th grade programs (~400 students/year; 98% minority and 60% high needs). Furthermore, through the National Multiple Sclerosis Foundation the DeSilva laboratory will hold a bi-annual lab tour and lecture to educate the community about advances in her laboratory on myelin research.
It is known that vesicular release of glutamate from axonal synapses induces glutamate receptor mediated currents in postsynaptic oligodendrocyte progenitor cells (OPCs). The goal of this project is to determine how this glutamatergic axon-glial signaling process promotes myelination. Preliminary data suggest that activity-dependent mechanisms generate action potentials causing axonal release of glutamate, which then activates glutamate receptors (AMPA receptors) on OPCs to elicit a mitogen-activated protein kinase (MAPK) signaling cascade, known to be important for myelination. The PI developed a novel in vivo approach to mechanistically link retinal ganglion cell activity with glutamatergic axon-OPC signaling in the optic nerve by either (a) regulating retinal ganglion cell action potentials or (b) inducibly deleting AMPA receptors on OPCs using a cell specific knockout mouse. Alterations in the phosphorylation state of the AMPA receptor-MAPK pathway in OPCs will be evaluated using fluorescence activated cell sorting. Perturbations in myelin thickness of axons in the optic nerve will be determined using electron microscopy. These measurements will elucidate sensitive periods when neuronal activity is necessary to promote AMPA receptor-MAPK signaling necessary for OPCs to mature and form the myelin sheath. Knowledge gained from these studies will establish a fundamental mechanism in axon-OPC communication with important ramifications for promoting central nervous system repair in multiple sclerosis.
