Loss of postsynaptic NMDARs drives nanoscale reorganization of Munc13-1 and PSD-95.

Synaptic transmission is shaped by the trans-synaptic coordination of molecular ensembles required for neurotransmitter release and receptor retention, but how receptors themselves influence this critical architecture remains unclear. Using state-of-the-art super-resolution microscopy, we report that loss of NMDA receptors from excitatory synapses alters both pre- and postsynaptic nano-organizational features. Notably, pharmacological antagonism of NMDA receptors also alters presynaptic features, but without fully mimicking effects of the knockout. This suggests that both NMDA receptor activity and presence at the synapse exert retrograde influence on active zone organization. Because numerous disease and activity states decrease expression or function of NMDA receptors, our results suggest that distinct nanostructural states contribute to the unique functional status of synapses in these disorders.