Abstract
ABSTRACTElectrical synapses (gap junctions) rapidly transmit signals between neurons and are composed of connexins. In neurons, connexin36 (Cx36) is the most abundant isoform; however, the mechanisms underlying formation of Cx36-containing electrical synapses are unknown. We focus on homocellular and heterocellular gap junctions formed by an AII amacrine cell, a key interneuron found in all mammalian retinas. In mice lacking native Cx36 but expressing a variant tagged with enhanced green fluorescent protein at the C-terminus (KO-Cx36-EGFP), heterocellular gap junctions formed between AII cells and ON cone bipolar cells are fully functional, whereas homocellular gap junctions between two AII cells are not formed. A tracer injected into an AII amacrine cell spreads into ON cone bipolar cells but is excluded from other AII cells. Reconstruction of Cx36–EGFP clusters on an AII cell in the KO-Cx36-EGFP genotype confirmed that the number, but not average size, of the clusters is reduced – as expected for AII cells lacking a subset of electrical synapses. Our studies indicate that some neurons exhibit at least two discriminatory mechanisms for assembling Cx36. We suggest that employing different gap-junction-forming mechanisms could provide the means for a cell to regulate its gap junctions in a target-cell-specific manner, even if these junctions contain the same connexin.
Highlights
Rapid signal propagation and processing are fundamental to the functioning of neuronal assemblies
The Cx36–EGFP fusion protein assembles into a subset of gap junctions in the KO-Cx36-EGFP retina The wild type (WT)-Cx36-EGFP mouse line has provided some clues to the mechanism of electrical synapse formation
Electrical synapses in the transgenic brain, which are visible as distinct fluorescent clusters, contain the Cx36–EGFP protein but the fusion protein will only assemble into gap junctions if neurons express an unaltered genomic copy of Cx36, presumably because an intact carboxy terminus is required for correct targeting or assembly (Christie et al, 2005; Helbig et al, 2010)
Summary
Rapid signal propagation and processing are fundamental to the functioning of neuronal assemblies. Electrical synapses (gap junctions), composed of connexin proteins (Cx), provide a fast means of inter-neuronal communication and are widely distributed in the central nervous system. Recent studies suggest that the regulation of electrical synapses might be very complex and dynamic (Flores et al, 2012; Kothmann et al, 2009): gap junctions are most likely to consist of multimolecular components (Li et al, 2012a) in which regulatory, cytoskeletal and scaffolding proteins participate in the regulation of conductance, assembly and turnover
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