Interplay of chemical neurotransmitters regulates developmental increase in electrical synapses

Abstract

Coupling of neurons by electrical synapses (gap junctions) transiently increases in the mammalian CNS during development. We report here that the developmental increase in neuronal gap junction coupling and expression of connexin 36 (C×36; neuronal gap junction protein) are regulated by an interplay between the activity of group II metabotropic glutamate receptors (mGluRs) and GABAA receptors. Specifically, using dye coupling, electrotonic coupling, Western blots and small interfering RNA in the rat and mouse hypothalamus and cortex in vivo and in vitro, we demonstrate that activation of group II mGluRs augments, and inactivation prevents, the developmental increase in neuronal gap junction coupling and C×36 expression. However, changes in GABAA receptor activity have the opposite effects. The regulation by group II mGluRs is via cAMP/PKA-dependent signaling, and regulation by GABAA receptors is via Ca2+/PKC-dependent signaling. Furthermore, the receptor-mediated upregulation of C×36 requires a neuron-restrictive silencer element in the C×36 gene promoter, and the downregulation involves the 3'-untranslated region of the C×36 mRNA, as shown using reverse-transcription quantitative real-time PCR and luciferase reporter activity analysis. In addition, the methyl thiazolyl tetrazolium analysis indicates that mechanisms for the developmental increase in neuronal gap junction coupling directly control the death/survival mechanisms in developing neurons. Together, the results suggest a multitiered strategy for chemical synapses in developmental regulation of electrical synapses © 2011 the authors.