The regulation and role of neuronal gap junctions during neuronal injury

Abstract

In the mammalian CNS, excessive release of glutamate and overactivation of glutamate receptors are responsible for the secondary (delayed) neuronal death following neuronal injury, including ischemia, traumatic brain injury (TBI) and epilepsy. The coupling of neurons by gap junctions (electrical synapses) increases during neuronal injury. In a recent study with the use of in vivo and in vitro models of cortical ischemia in mice, we have demonstrated that the ischemic increase in neuronal gap junction coupling is regulated by glutamate via group II metabotropic glutamate receptors (mGluR). Specifically, we found that activation of group II mGluRs increases background levels of neuronal gap junction coupling and expression of connexin 36 (Cx36; neuronal gap junction protein), whereas inactivation of group II mGluRs prevents the ischemia-mediated increases in the coupling and Cx36 expression. Using the analysis of neuronal death, we also established that inactivation of group II mGluRs or genetic elimination of Cx36 both dramatically reduce ischemic neuronal death in vitro and in vivo. Similar results were obtained using in vitro models of TBI and epilepsy. Our study demonstrated that mechanisms for the injury-mediated increase in neuronal gap junction coupling are part of the mechanisms for glutamate-dependent neuronal death.

Figure 1. Glutamate-dependent excitotoxicity during neuronal injuries. (A) Traditional model of the mechanisms for glutamate-dependent excitotoxicity. (B) Novel model of the mechanisms of glutamate-dependent excitotoxicity. b1: Existing neuronal gap junctions (GJ) contribute substantially to neuronal death caused by overactivation of NMDARs. b2: New neuronal gap junctions are induced by activation of group II mGluRs (IImGluRs) and also contribute to glutamate-dependent neuronal death. ⊕, this sign indicates the increase in the receptor activity or expression of Cx36. See text for details. Figure reprinted with permission: Wang Y, Song J-H, Denisova JV, Park W-M, Fontes JD, Belousov AB. Neuronal gap junction coupling is regulated by glutamate and plays critical role in cell death during neuronal injury. J Neurosci 2012; 32:713-25; PMID:22238107; 10.1523/jeurosci.3872-11.2012.