Abstract:

In the mammalian CNS coupling of neurons by gap junctions and the expression of neuronal gap junction protein, connexin 36 (Cx36) rapidly increase (usually during 1-2 hours) following a wide range of neuronal injuries, including ischemia, traumatic brain injury (TBI), spinal cord injury, epilepsy and inflammation. Pharmacological blockade or genetic elimination of Cx36-containing gap junctions dramatically reduce neuronal death in animal models of ischemia, TBI and epilepsy and prevent NMDA receptor (NMDAR)-mediated excitotoxicity. This suggests a critical role for neuronal gap junctions in the mechanisms of neuronal death. In our recent study, we addressed the following three questions. Are changes in the expression of Cx36 directly affect neuronal death? Is the contribution of Cx36 to neuronal death depends on channel activity of gap junctional complexes among neurons or it is channel-independent? Do neuronal hemichannels contribute to neuronal death? In conclusion, this study provided insight into the mechanisms of contribution of neuronal gap junctions in NMDAR-dependent excitotoxicity and ischemic neuronal death. Because clinical trials for NMDAR antagonists as neuroprotective agents largely failed, the study suggested that another important therapeutic target for the development of new neuroprotective agents can be neuronal gap junction coupling.