The regulation and role of neuronal gap junctions during development

Abstract

Coupling of neurons by electrical synapses (gap junctions) transiently increases in the mammalian CNS during development and plays a role in a number of developmental events, including neuronal death. The coupling subsequently decreases and remains low in the adult, confined to specific subsets of neurons. In a recent study we have demonstrated that the developmental increase in neuronal gap junction coupling is regulated by the balance between the activity of two neurotransmitter receptors, group II metabotropic glutamate receptors (mGluR) and GABA_A receptors. Specifically, we found that activation of group II mGluRs induces the developmental increases in neuronal gap junction coupling and expression of connexin 36 (Cx36; neuronal gap junction protein) and activation of GABA_A receptors counteracts to these increases. We also established that the regulation by both neurotransmitter receptors is via a neuron-restrictive silencer element in the Cx36 gene promoter and the 3'-untranslated region of the Cx36 mRNA. Importantly, we demonstrated that mechanisms for the developmental increase in neuronal gap junction coupling directly control the death/survival mechanisms in developing neurons.

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Acknowledgments

I thank the contributors to this study: Won-Mee Park, Dr. Yongfu Wang, Dr. Soodong Park, Janna V. Denisova and Dr. Joseph D. Fontes. This research was supported by NIH (R01 NS064256).

Figures and Tables

Figure 1 Simplified model of mechanisms for the developmental increase in neuronal gap junction coupling and connexin 36 expression in the mammalian CNS. Note that in developing neurons, the GABA_AR-dependent pathway is excitatory and causes cell depolarization and Ca²⁺ influx. cAMP, cyclic AMP; GABA_AR, GABA_A receptor; IImGlur, group II metabotropic glutamate receptor; nGJ/Cx36, neuronal gap junction coupling and connexin 36; NRSE, neuron-restrictive silencer element; PKA, protein kinase A; PKC, protein kinase C; 3′UTR, 3′-untranslated region; VGCC, voltage-gated Ca²⁺ channels; ⊕, activation of group II mGluRs or GABA_ARs; ⊖, inactivation of group II mGluRs or GABA_ARs; ↑, increase; ↓, decrease. See text for details.

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