Upregulation of EphA4 on astrocytes potentially mediates astrocytic gliosis after cortical lesion in the marmoset monkey.

Glial scar formation occurs in response to brain injury in mammalian models and inhibits axonal growth. Identification of molecules that may mediate reactivity of astrocytes has become a leading therapeutic goal in the field of neurotrauma. In adult rodent brain and spinal cord, many of the Eph receptors and their ephrin ligands have been demonstrated to be upregulated on reactive astrocytes at the injury site; however, little is known about the expression of these molecules in nonhuman primate injury models. This study examines the role of the tyrosine kinase EphA4 receptor, which predominantly binds most ephrin ligands, after injury in marmoset monkey brain. Following lesioning of the primary visual cortex (V1) in the adult marmoset, EphA4 is strongly upregulated on reactive astrocytes around the lesion site, which secrete extracellular matrix molecules such as chondroitin sulfate proteoglycans, which are known for their inhibitory effect on axonal growth and regeneration. This astrocyte reactivity was also associated with neuronal death in the area adjacent to the lesion site. EphA4 activation induced by clustered ephrin A5-Fc-mediated astrocyte proliferation and glial fibrillary acidic protein expression in vitro, as demonstrated by closure of scratched wound and MTT assays, occurs via two potential signaling pathways, the mitogen-activated protein kinase and Rho pathways. These results in a nonhuman primate model highlight the importance of developing pharmacotherapeutic approaches to block these molecules following brain injury.