Synaptic nanomodules underlie the organization and plasticity of spine synapses

Experience results in long-lasting changes in dendritic spine size, yet how the molecular architecture of the synapse responds to plasticity remains poorly understood. Here, a combined approach of multi-color stimulated emission depletion microscopy (STED) and confocal imaging demonstrates that structural plasticity is linked to the addition of unitary synaptic nanomodules to spines. Spine synapses in vivo and in vitro contain discrete and aligned sub-diffraction modules of pre- and post-synaptic proteins whose number scales linearly with spine volume. Live-cell time-lapse super-resolution imaging reveals that N-methyl-D-aspartate receptor (NMDAR)-dependent increases in spine size are accompanied both by enhanced mobility of pre- and post-synaptic modules that remain aligned with each other and by the coordinated addition of new nanomodules. These findings suggest a simplified model for experience-dependent structural plasticity relying on an unexpectedly modular nano-molecular architecture of synaptic proteins.