Nanoscale 3D EM reconstructions reveal intrinsic mechanisms of structural diversity of chemical synapses

Chemical synapses of shared cellular origins have remarkably heterogeneous structures, but how this diversity is generated is unclear. Here, we use three-dimensional (3D) electron microscopy and artificial intelligence algorithms for image processing to reconstruct functional excitatory microcircuits in the mouse hippocampus and microcircuits in which neurotransmitter signaling is permanently suppressed with genetic tools throughout the lifespan. These nanoscale analyses reveal that experience is dispensable for morphogenesis of synapses with different geometric shapes and contents of membrane organelles and that arrangement of morphologically distinct connections in local networks is stochastic. Moreover, loss of activity increases the variability in sizes of opposed pre- and postsynaptic structures without disrupting their alignments, suggesting that inherently variable weights of naive connections become progressively matched with repetitive use. These results demonstrate that mechanisms for the structural diversity of neuronal synapses are intrinsic and provide insights into how circuits essential for memory storage assemble and integrate information.