Activity-dependent synapse clustering underlies eye-specific competition in the developing retinogeniculate system

Abstract

Co-active synaptic connections are often spatially clustered to enable local dendritic computations underlying learning, memory, and basic sensory processing. In the mammalian visual system, retinal ganglion cell (RGC) axons converge to form clustered synaptic inputs for local signal integration in the dorsal lateral geniculate nucleus (dLGN) of the thalamus. Retinogeniculate synapse clustering is promoted by visual experience after eye-opening, but the earliest events in cluster formation and potential regulation by spontaneous retinal wave activity prior to visual experience are unknown. Here, using volumetric super-resolution single-molecule localization microscopy together with eye-specific labeling of developing retinogeniculate synapses in the mouse, we show that synaptic clustering is eye-specific and activity-dependent during the first postnatal week. We identified a subset of complex retinogeniculate synapses with larger presynaptic vesicle pools and multiple active zones that simultaneously promote the clustering of like-eye synapses (synaptic stabilization) and prohibit synapse clustering from the opposite eye (synaptic punishment). In mutant mice with disrupted spontaneous retinal wave activity, complex synapses form, but fail to drive eye-specific synaptic clustering and punishment seen in controls. These results highlight a role for spontaneous retinal activity in regulating eye-specific stabilization and punishment signals contributing to synaptic clustering in circuits essential for visual perception and behavior.