title: 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 (Cx36; neuronal gap junction protein) are regulated by an interplay between the activity of group II metabotropic glutamate receptors (mGluRs) and GABA(A) 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 Cx36 expression. However, changes in GABA(A) receptor activity have the opposite effects. The regulation by group II mGluRs is via cAMP/PKA-dependent signaling, and regulation by GABA(A) receptors is via Ca(2+)/PKC-dependent signaling. Furthermore, the receptor-mediated upregulation of Cx36 requires a neuron-restrictive silencer element in the Cx36 gene promoter, and the downregulation involves the 3'-untranslated region of the Cx36 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.
authors.affiliation: Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, Kansas 66160, USA.
authors.forename: Won-Mee
authors.initials: WM
authors.lastname: Park
authors.forename: Yongfu
authors.initials: Y
authors.lastname: Wang
authors.forename: Soodong
authors.initials: S
authors.lastname: Park
authors.forename: Janna V
authors.initials: JV
authors.lastname: Denisova
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Fontes
authors.forename: Andrei B
authors.initials: AB
authors.lastname: Belousov
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D002450:Cell Communication / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000196:embryology / Q000378:metabolism*; D017630:Connexins / Q000235:genetics / Q000378:metabolism*; D054351:Electrical Synapses / Q000378:metabolism*; D005260:Female; D007031:Hypothalamus / Q000196:embryology / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism*; D018377:Neurotransmitter Agents / Q000378:metabolism*; D034741:RNA, Small Interfering; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D009435:Synaptic Transmission / Q000502:physiology; D000097004:Gap Junction delta-2 Protein
chemical_list: D017630:Connexins; D018377:Neurotransmitter Agents; D034741:RNA, Small Interfering; D018094:Receptors, Metabotropic Glutamate; D000097004:Gap Junction delta-2 Protein