Neurons are highly polarized cells with axons and dendrites. ), offering multiple binding sites for GlyRs and representing a structure for new gephyrin molecules to be added (see Figure 1 It has been postulated that this arrangement leads to the formation of a hexagonal lattice in the postsynaptic density ( Xiang et al., 2001 Actually, gephyrin molecules are able to trimerize and dimerize simultaneously via its G- and E-domains, respectively ( Sola et al., 2001 The same consequence is observed in the gephyrin-deficient mouse ( Feng et al., 1998 Disruption of the gephyrin scaffold by antisense oligonucleotides or after intracellular antibody capture prevents the formation of GlyR clusters ( Kirsch et al., 1993a ) and requires the presence of the appropriate presynaptic innervation ( Lévi et al., 1999 The recruitment of GlyR by gephyrin within clusters depends on a functional receptor ( Kirsch and Betz, 1998 Synaptic gephyrin clustering precedes the postsynaptic localization of GlyRs in vivo as well as in vitro ( Kirsch et al., 1993b The first evidence of a functional synaptic microdomain was the detection by light and electron microscopy of GlyR and gephyrin aggregates in front of the presynaptic bouton ( Triller et al., 1985 In addition to its association with GlyR during intracellular transport, gephyrin stabilizes the receptor once inserted in the surface membrane, in particular at synaptic sites. ), which apply gephyrin as a cargo adaptor and link the receptor to microtubule-dependent motor proteins that power long distance bidirectional transport between neuronal somata and distal neurites ( Maas et al., 2006 GlyR molecules are associated with gephyrin in intracellular vesicles ( Hanus et al., 2004 GlyRs bind directly the scaffold protein gephyrin ( Meyer et al., 1995 ) or mixed glycinergic/GABAergic postsynaptic sites ( Lévi et al., 1999 Glycine receptors (GlyRs) mediate synaptic inhibition in brain and spinal neurons and locate either at glycinergic ( Triller et al., 1985 Here, we review (i) proteins and mechanisms involved in GlyR cytoskeletal transport, (ii) the diffusion dynamics of GlyR and of its scaffolding protein gephyrin that control receptor numbers, and its relationship with synaptic plasticity, and (iii) adaptative changes in GlyR diffusion in response to global activity modifications, as a homeostatic mechanism. In recent years, results obtained from several groups studying glycine receptor (GlyR) trafficking and dynamics shed light on the regulation of synaptic GlyR density. In parallel, lateral diffusion events along the plasma membrane allow the exchange of receptor molecules between synaptic and extrasynaptic compartments, contributing to synaptic strength regulation. This can be achieved either through plasma membrane insertion of receptors derived from intracellular vesicle pools, a process depending on active cytoskeleton transport, or through surface membrane removal via endocytosis. One way to modulate synaptic strength is to regulate neurotransmitter receptor numbers at postsynaptic sites. Regulation of synaptic transmission is essential to tune individual-to-network neuronal activity.
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