Abstract
The physiological functions of glycine receptors (GlyRs) depend on their subcellular locations. In axonal terminals of the central neurons, GlyRs trigger a slow facilitation of presynaptic transmitter release; however, their spatial relationship to the release sites is not known. In this study, we examined the distribution of GlyRs in the rat glutamatergic calyx of Held nerve terminal using high-resolution pre-embedding immunoelectron microscopy. We performed a quantitative analysis of GlyR-associated immunogold (IG) labeling in 3D reconstructed calyceal segments. A variable density of IG particles and their putative accumulations, inferred from the frequency distribution of inter-IG distances, indicated a non-uniform distribution of the receptors in the calyx. Subsequently, increased densities of IG particles were found in calyceal swellings, structures characterized by extensive exocytosis of glutamate. In swellings as well as in larger calyceal stalks, IG particles did not tend to accumulate near the glutamate releasing zones. On the other hand, GlyRs in swellings (but not in stalks) preferentially occupied membrane regions, unconnected to postsynaptic cells and presumably accessible by ambient glycine. Furthermore, the sites with increased GlyR concentrations were found in swellings tightly juxtaposed with GABA/glycinergic nerve endings. Thus, the results support the concept of an indirect mechanism underlying the modulatory effects of calyceal GlyRs, activated by glycine spillover. We also suggest the existence of an activity-dependent mechanism regulating the surface distribution of α homomeric GlyRs in axonal terminals of central neurons.
Highlights
The subcellular distribution of ligand-gated ion channels (LGICs) in neuronal cells is tightly correlated with the physiological functions of the receptors
NON-UNIFORM DISTRIBUTION OF glycine receptors (GlyRs) AT THE CALYX OF HELD NERVE TERMINAL To reveal the surface distribution of presynaptic GlyRs, we performed a quantitative analysis of their plasma membraneassociated labeling with anti-GlyRα1-coupled IG particles in
The latter staining pattern is typical for somatodendritic GlyRs that accumulate in synaptic contacts between inhibitory boutons and MNTB PC (Hruskova et al, 2012)
Summary
The subcellular distribution of ligand-gated ion channels (LGICs) in neuronal cells is tightly correlated with the physiological functions of the receptors. Somatodendritic receptors reside at subsynaptic sites, generating fast and phasic responses to synaptic transmitters, as well as in extrasynaptic compartments, where they mediate slow or tonic modulation of neuronal activity (Farrant and Nusser, 2005; Muller et al, 2008; Hardingham and Bading, 2010; Vizi et al, 2010; Brickley and Mody, 2012; Kopach and Voitenko, 2013). Little is known about the localization of LGIC in the plasma membrane of presynaptic nerve terminals These receptors mediate relatively slow modulation of presynaptic exocytosis and plasticity, and their physiological activation often results from the spillover of neurotransmitters (Danbolt, 2001; Kullmann, 2001; Boehm and Kubista, 2002; Engelman and MacDermott, 2004; Pinheiro and Mulle, 2008; Trigo et al, 2008; Verhoog and Mansvelder, 2011). The surface distribution of LGIC in presynaptic nerve terminals would be expected to be similar to that of extrasynaptic receptors in somatodendritic compartments (Kieval et al, 2001; Belenky et al, 2003; Darstein et al, 2003; Ruiz et al, 2003; Jourdain et al, 2007)
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