title: Nanoscale Structural Plasticity of the Active Zone Matrix Modulates Presynaptic Function.
abstract: The active zone (AZ) matrix of presynaptic terminals coordinates the recruitment of voltage-gated calcium channels (VGCCs) and synaptic vesicles to orchestrate neurotransmitter release. However, the spatial organization of the AZ and how it controls vesicle fusion remain poorly understood. Here, we employ super-resolution microscopy and ratiometric imaging to visualize the AZ structure on the nanoscale, revealing segregation between the AZ matrix, VGCCs, and putative release sites. Long-term blockade of neuronal activity leads to reversible AZ matrix unclustering and presynaptic actin depolymerization, allowing for enrichment of AZ machinery. Conversely, patterned optogenetic stimulation of postsynaptic neurons retrogradely enhanced AZ clustering. In individual synapses, AZ clustering was inversely correlated with local VGCC recruitment and vesicle cycling. Acute actin depolymerization led to rapid (5 min) nanoscale AZ matrix unclustering. We propose a model whereby neuronal activity modulates presynaptic function in a homeostatic manner by altering the clustering state of the AZ matrix.
authors.affiliation: Wolfson Centre for Age-Related Diseases, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE1 1UL, UK; Centre For Developmental Neurobiology, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE1 1UL, UK. Electronic address: oleg.glebov@kcl.ac.uk.
authors.forename: Oleg O
authors.initials: OO
authors.lastname: Glebov
authors.affiliation: Centre For Developmental Neurobiology, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE1 1UL, UK.
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Jackson
authors.affiliation: Randall Division of Molecular Biophysics, Faculty of Life Sciences and Medicine, King's College London, London SE1 1UL, UK.
authors.forename: Christian M
authors.initials: CM
authors.lastname: Winterflood
authors.affiliation: Randall Division of Molecular Biophysics, Faculty of Life Sciences and Medicine, King's College London, London SE1 1UL, UK; Department of Physics, Faculty of Natural and Mathematical Sciences, King's College London, London WC2R 2LS, UK.
authors.forename: Dylan M
authors.initials: DM
authors.lastname: Owen
authors.affiliation: School of Biochemistry, University of Bristol, Bristol BS8 1TD, UK.
authors.forename: Ellen A
authors.initials: EA
authors.lastname: Barker
authors.affiliation: Wolfson Centre for Age-Related Diseases, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE1 1UL, UK.
authors.forename: Patrick
authors.initials: P
authors.lastname: Doherty
authors.affiliation: Randall Division of Molecular Biophysics, Faculty of Life Sciences and Medicine, King's College London, London SE1 1UL, UK; Institute of Chemistry and Biochemistry, Freie Universität Berlin, 14195 Berlin, Germany.
authors.forename: Helge
authors.initials: H
authors.lastname: Ewers
authors.affiliation: Centre For Developmental Neurobiology, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE1 1UL, UK. Electronic address: juan.burrone@kcl.ac.uk.
authors.forename: Juan
authors.initials: J
authors.lastname: Burrone
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D002186:Cannabinoids / Q000378:metabolism; D016000:Cluster Analysis; D021621:Imaging, Three-Dimensional; D008954:Models, Biological; D053758:Nanoparticles / Q000737:chemistry*; D009473:Neuronal Plasticity / Q000502:physiology*; D017729:Presynaptic Terminals / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D000199:Actins; D002186:Cannabinoids; D016194:Receptors, N-Methyl-D-Aspartate
keywords: super-resolution microscopy; synaptic plasticity