Gephyrin and the regulation of synaptic strength and dynamics at glycinergic inhibitory synapses

Glycinergic synapses predominate in brainstem and spinal cord where they modulate motor and sensory processing. Their postsynaptic mechanisms have been considered rather simple because they lack a large variety of glycine receptor isoforms and have relatively simple postsynaptic densities at the ultrastructural level. However, this simplicity is misleading being their postsynaptic regions regulated by a variety of complex mechanisms controlling the efficacy of synaptic inhibition. Early studies suggested that glycinergic inhibitory strength and dynamics depend largely on structural features rather than on molecular complexity. These include regulation of the number of postsynaptic glycine receptors, their localization and the amount of co-localized GABA_A receptors and GABA-glycine co-transmission. These properties we now know are under the control of gephyrin. Gephyrin is the first postsynaptic scaffolding protein ever discovered and it was recently found to display a large degree of variation and regulation by splice variants, posttranslational modifications, intracellular trafficking and interactions with the underlying cytoskeleton. Many of these mechanisms are governed by converging excitatory activity and regulate gephyrin oligomerization and receptor binding, the architecture of the postsynaptic density (and by extension the whole synaptic complex), receptor retention and stability. These newly uncovered molecular mechanisms define the size and number of gephyrin postsynaptic regions and the numbers and proportions of glycine and GABA_A receptors contained within. All together, they control the emergence of glycinergic synapses of different strength and temporal properties to best match the excitatory drive received by each individual neuron or local dendritic compartment.