Loss of white matter at the site of traumatic spinal cord injury (SCI) interrupts critical ascending and descending tracts and thus precludes normal function in the spinal cord distal to the site of injury. In the last project period we identified a previously unrecognized process involved in the loss of functional white matter: the AMPA receptor-mediated loss of oligodendrocytes. Approximately twice as much white matter is spared in a standardized contusion SCI model when glial loss is inhibited with the AMPA receptor antagonist, NBQX. Our data support a new understanding of the critical role oligodendrocytes play in trophic support of axons. We have examined the effect of SCI on endogenous glial precursor cell (GPC) populations in vivo, developed an in vitro model to study these cells and identified glial growth factor 2 (GGF2) as an important mitogen for GPC cells in vitro and in vivo. In the new project period we propose to investigate the hypothesis that the endogenous GPCs can be experimentally manipulated to improve recovery of function after incomplete SCI. We have three specific aims. (I) Test the effect of increasing endogenous GPC proliferation on functional recovery in a clinically relevant in vivo model of SCI in the rat.We will compare functional recovery and chronic histopathology in rats that receive GGF2 beginning at different times after SCI, and with or without FGF2 that may produce increased proliferation, or acute TTX treatment that we have shown preserves axons per se. (II). Evaluate the mechanism(s) through which increasing endogenous GPCs with GGF2 improves functional recovery after SCI in the rat,including effects on cell proliferation, survival and differentiation as well as chronic white matter pathology and preservation of axons. (Ill)Develop and use a model of SCI in mice expressing enhanced green fluorescent protein (EGFP) under the control of the CNP promoter that is expressed in glial progenitors to critically evaluate the temporal-spatial effect of SCI on GPC electrophysiological and immunocytochemical phenotypes in situ in tissue slices and the effect of treatment with GGF2 on these properties. We will gain new information about whether endogenous GPCs can be manipulated after SCI to enhance functional recovery. As SCI and brain injury create devastatingand permanent functional deficits for large numbers of Americans, and such injury is especially prevalent in young people and leads to life-long disabilities, therapies to enhance recovery will benefit public health.
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