Neuroligin-3 confines AMPA receptors into nanoclusters, thereby controlling synaptic strength at the calyx of Held synapses

Abstract

The subsynaptic organization of postsynaptic neurotransmitter receptors into nanoclusters that are aligned with presynaptic release sites is essential for the high fidelity of synaptic transmission. However, the mechanisms controlling the nanoscale organization of neurotransmitter receptors in vivo remain incompletely understood. Here, we deconstructed the role of neuroligin-3 (Nlgn3), a postsynaptic adhesion molecule linked to autism, in organizing AMPA-type glutamate receptors in the calyx of Held synapse. Deletion of Nlgn3 lowered the amplitude and slowed the kinetics of AMPA receptor–mediated synaptic responses. Super-resolution microscopy revealed that, unexpectedly, these impairments in synaptic transmission were associated with an increase in the size of postsynaptic PSD-95 and AMPA receptor nanoclusters but a decrease of the densities in these clusters. Modeling showed that a dilution of AMPA receptors into larger nanocluster volumes decreases synaptic strength. Nlgn3, likely by binding to presynaptic neurexins, thus is a key organizer of AMPA receptor nanoclusters that likely acts via PSD-95 adaptors to optimize the fidelity of synaptic transmission.

Nanoscale reorganisation of synaptic proteins in Alzheimer's disease

“…These differences suggest that a distinct set of signalling cascades underlies postsynaptic reorganisation by Aβ treatment compared with that during LTD. More importantly, Aβ-treated synapses showed a significant reduction in the local enrichment of GluA1 and PSD-95 to RIM nanoclusters compared with the controls. Because adhesion molecules have been shown to mediate transsynaptic nanoalignment, [16,19,21] this reduction in transsynaptic protein enrichment may result from alterations in adhesion molecules by Aβ. [50] Cultured primary neurons incubated with soluble Aβ oligomers have been widely used as an in vitro model to feature AD pathologies.…”

“…[17] These nano-architectures are undergoing vigorous reorganisation during synaptic plasticity and development, [17,21] and disruption of these organisations leads to deficient transmission both in vitro [16,19] and in vivo. [21] Despite the significant modulation of synaptic functions by these subsynaptic nano-organisations, it is still unknown how these synaptic nanoarchitectures are reorganised in pathological conditions such as AD.…”

Expression and structural analysis of human neuroligin 2 and neuroligin 3 implicated in autism spectrum disorders

“…The functional difference between NLGN2 and NLGN3 indicated that their small structural differences may cause a huge functional gap. Our results showed that the differences in interface area and orientation are the small structural differences between NLGN2 and NLGN3, which possibly confer the ability of NLGN2 to determine inhibitory synaptic transmission in neurons ( 23 ) and confer the ability of NLGN3 to control AMPAR-mediated basal excitatory transmission ( 69 ). Taken together with the previously reported complex structure of NLGN2 and MDGA1 ( 40 ), it is possible that the different orientations of NLGNs may also affect their interactions with MDGAs.…”

CASK and FARP localize two classes of post-synaptic ACh receptors thereby promoting cholinergic transmission

“…To become functional, assembled ionotropic receptors must be transported to the plasma membrane and clustered at post-synaptic elements, where they are immobilized by synaptic scaffolding proteins. In rodents, several scaffolding proteins have been identified for localizing ionotropic GABA (neuroligin 2, collybistin, gephyrin) [8][9][10], glutamate (PSD95, neuroligin 1 and 3) [11][12][13], and ACh (rapsyn, MuSK) receptors [14,15]. Analysis of invertebrate synapses have identified additional synaptic scaffolds.…”