The astrocytic response to CNS injury is complex and multifaceted, with important implications for protecting vulnerable neurons from cell death. Although specific neuroprotective functions of astrocytes, e.g., glutamate transport, are known to be energy dependent, little is known about how, or if, astrocytes alter their bioenergetic state in response to injury. We have discovered that expression of the Adenine Nucleotide Translocator-1 (Ant1) by reactive astrocytes increases after cortical injury and that this increase is mediated by the injury-induced cytokine transforming growth factor beta1(TGF-beta1). Ant1 is an inner mitochondrial membrane protein that exchanges mitochondrial ATP for cytosolic ADP, thereby regulating the supply of the substrate required for continued mitochondrial energy production (ADP) as well as the delivery of ATP to the cytosol for energy dependent functions. Importantly, the expression of the closely related isoform, Ant2, does not appear to change. Additional preliminary data demonstrate that glutamate uptake by Ant1 null astrocytes is significantly impaired and that Ant1 null mutant animals are prone to cortical damage following combined hypoxic/ischemic injury. These data suggest that reactive astrocytes experience a bioenergetic demand and are consistent with the hypothesis that Ant1 is a critical component of the astrocytic response to injury by mobilizing the energy required during reactive astrogliosis. This hypothesis will be tested in vitro and in an in vivo model of cerebral hypoxic/ischemic injury in Ant1 null mutant, Ant2 neural null transgenic, and genetically matched control mice. To test this hypothesis, we will: (1) examine whether astrocytic Ant1 is required to protect neurons from excitotoxic injury or death in vitro, by focusing on the critical astrocytic function of glutamate uptake; and (2) determine if astrocytic Ant1 expression is required for neuronal survival in vivo after hypoxic/ischemic injury. These studies will provide important mechanistic insight into the biological response of reactive astrocytes by examining the requirement for a molecule that facilitates mitochondrial ATP production and mobilization.
| Olson, Ellen E; Lyuboslavsky, Polina; Traynelis, Stephen F et al. (2004) PAR-1 deficiency protects against neuronal damage and neurologic deficits after unilateral cerebral hypoxia/ischemia. J Cereb Blood Flow Metab 24:964-71 |
