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Sci Rep. 2016 Apr 25;6:24626. doi: 10.1038/srep24626.

PSD95 nanoclusters are postsynaptic building blocks in hippocampus circuits.

Author information

Centre for Clinical Brain Sciences (CCBS), University of Edinburgh, Edinburgh, United Kingdom.
Edinburgh Super-Resolution Imaging Consortium (ESRIC), Heriot Watt University, Edinburgh, United Kingdom.
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW. United Kingdom.
Cambridge Advanced Imaging Centre (CAIC), University of Cambridge, Cambridge, United Kingdom.
Instituto Cajal (CSIC) and Centro de Tecnología Biomédica (UPM), Madrid, Spain.
Synome Ltd, Babraham Research Campus, Cambridge, United Kingdom.
Institute of Biological Chemistry, Biophysics and Bioengineering, Heriot-Watt University, Edinburgh, EH14 4AS, UK.


The molecular features of synapses in the hippocampus underpin current models of learning and cognition. Although synapse ultra-structural diversity has been described in the canonical hippocampal circuitry, our knowledge of sub-synaptic organisation of synaptic molecules remains largely unknown. To address this, mice were engineered to express Post Synaptic Density 95 protein (PSD95) fused to either eGFP or mEos2 and imaged with two orthogonal super-resolution methods: gated stimulated emission depletion (g-STED) microscopy and photoactivated localisation microscopy (PALM). Large-scale analysis of ~100,000 synapses in 7 hippocampal sub-regions revealed they comprised discrete PSD95 nanoclusters that were spatially organised into single and multi-nanocluster PSDs. Synapses in different sub-regions, cell-types and locations along the dendritic tree of CA1 pyramidal neurons, showed diversity characterised by the number of nanoclusters per synapse. Multi-nanocluster synapses were frequently found in the CA3 and dentate gyrus sub-regions, corresponding to large thorny excrescence synapses. Although the structure of individual nanoclusters remained relatively conserved across all sub-regions, PSD95 packing into nanoclusters also varied between sub-regions determined from nanocluster fluorescence intensity. These data identify PSD95 nanoclusters as a basic structural unit, or building block, of excitatory synapses and their number characterizes synapse size and structural diversity.

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