Nanoscale 3D EM reconstructions reveal intrinsic mechanisms of structural diversity of chemical synapses
Yongchuan Zhu,
Marco Uytiepo,
Eric Bushong,
Matthias Haberl,
Elizabeth Beutter,
Frederieke Scheiwe,
Weiheng Zhang,
Lyanne Chang,
Danielle Luu,
Brandon Chui,
Mark Ellisman,
Anton Maximov
Affiliations
Yongchuan Zhu
Department of Neuroscience, The Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA 92037, USA
Marco Uytiepo
Department of Neuroscience, The Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA 92037, USA
Eric Bushong
National Center for Microscopy and Imaging Research, University of California, San Diego, CA 92037, USA; Department of Neurosciences, University of California, San Diego, School of Medicine, La Jolla, CA 92037, USA
Matthias Haberl
National Center for Microscopy and Imaging Research, University of California, San Diego, CA 92037, USA; Department of Neurosciences, University of California, San Diego, School of Medicine, La Jolla, CA 92037, USA
Elizabeth Beutter
Department of Neuroscience, The Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA 92037, USA
Frederieke Scheiwe
Department of Neuroscience, The Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA 92037, USA
Weiheng Zhang
Department of Neuroscience, The Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA 92037, USA
Lyanne Chang
Department of Neuroscience, The Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA 92037, USA
Danielle Luu
Department of Neuroscience, The Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA 92037, USA
Brandon Chui
Department of Neuroscience, The Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA 92037, USA
Mark Ellisman
National Center for Microscopy and Imaging Research, University of California, San Diego, CA 92037, USA; Department of Neurosciences, University of California, San Diego, School of Medicine, La Jolla, CA 92037, USA; Corresponding author
Anton Maximov
Department of Neuroscience, The Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA 92037, USA; Corresponding author
Summary: 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.
