Astrocytes respond to spinal cord injury (SCI) by altered gene expression, hypertrophy and proliferation, a process known as reactive astrocytosis. Considerable descriptive information is available about molecules produced by reactive astrocytes, but the functions of these cells are not well understood. Astrocyte scars are thought to prevent axon regeneration after SCL but evidence also points towards important potential roles for reactive astrocytes in the process of acute local tissue repair. We have developed an experimental model to demonstrate specific functions of reactive astrocytes by targeting the specific ablation of this cell type after CNS injury in transgenic mice. Using these mice we have shown that after injury in the forebrain, reactive astrocytes are essential for protection of local neurons, repair of the blood brain barrier and restricting the infiltration of inflammatory white blood cells. In addition, we found increased local sprouting of axons in areas where reactive astrocytes were ablated. In this proposal we will apply this transgenic model to study the roles of reactive astrocytes in SCI. First, we will ablate reactive scar-forming astrocytes at the site of a small, acute spinal cord lesion to characterize the roles played by these cells in (i) the acute injury response and repair process after SCI, and (ii) long term effects on nerve fiber tract integrity and capacity for regrowth. These findings will tell us whether reactive, scar-forming astrocytes are, as we predict, essential for acute tissue repair after SCI, such that their absence or dysfunction will markedly exacerbate the tissue degeneration and detrimental effects associated with small spinal cord lesions. Next, we will determine the extent of axon survival and capacity for local and long distance axon regeneration in the transected dorsal columns of the spinal cord, after transgenically-targeted ablation of reactive scar-forming astrocytes, alone or in combination with grafts of immature astrocytes, neural stem cells or olfactory ensheathing cells. These findings will tell us whether ablation and appropriate replacement of reactive, scar-forming astrocytes can, as we predict, lead to substantially improved regrowth of transected long tract axons after acute SCI. Together, information from these studies will provide essential ground work for future dissection of the underlying molecular signaling mechanisms that mediate specifically identified roles (both beneficial and detrimental) of reactive astrocytes after SCI.
