title: Extensive remodeling of the presynaptic cytomatrix upon homeostatic adaptation to network activity silencing.
abstract: Global changes of activity in neuronal networks induce homeostatic adaptations of synaptic strengths, which involve functional remodeling of both presynaptic and postsynaptic apparatuses. Despite considerable advances in understanding cellular properties of homeostatic synaptic plasticity, the underlying molecular mechanisms are not fully understood. Here, we explored the hypothesis that adaptive homeostatic adjustment of presynaptic efficacy involves molecular remodeling of the release apparatus including the presynaptic cytomatrix, which spatially and functionally coordinates neurotransmitter release. We found significant downregulation of cellular expression levels of presynaptic scaffolding proteins Bassoon, Piccolo, ELKS/CAST, Munc13, RIM, liprin-α, and synapsin upon prolonged (48 h) activity depletion in rat neuronal cultures. This was accompanied by a general reduction of Bassoon, Piccolo, ELKS/CAST, Munc13, and synapsin levels at synaptic sites. Interestingly, RIM was upregulated in a subpopulation of synapses. At the level of individual synapses, RIM quantities correlated well with synaptic activity, and a constant relationship between RIM levels and synaptic activity was preserved upon silencing. Silencing also induced synaptic enrichment of other previously identified regulators of presynaptic release probability, i.e., synaptotagmin1, SV2B, and P/Q-type calcium channels. Seeking responsible cellular mechanisms, we revealed a complex role of the ubiquitin-proteasome system in the functional presynaptic remodeling and enhanced degradation rates of Bassoon and liprin-α upon silencing. Together, our data indicate a significant molecular reorganization of the presynaptic release apparatus during homeostatic adaptation to network inactivity and identify RIM, synaptotagmin1, Ca(v)2.1, and SV2B as molecular candidates underlying the main silencing-induced functional hallmark at presynapse, i.e., increase of neurotransmitter release probability.
authors.affiliation: Department of Neurochemistry and Molecular Biology, and Research Group Molecular Physiology, Leibniz Institute for Neurobiology, D-39118 Magdeburg, Germany.
authors.forename: Vesna
authors.initials: V
authors.lastname: Lazarevic
authors.forename: Cornelia
authors.initials: C
authors.lastname: Schöne
authors.forename: Martin
authors.initials: M
authors.lastname: Heine
authors.forename: Eckart D
authors.initials: ED
authors.lastname: Gundelfinger
authors.forename: Anna
authors.initials: A
authors.lastname: Fejtova
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism; D015536:Down-Regulation / Q000502:physiology; D009415:Nerve Net / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009473:Neuronal Plasticity / Q000502:physiology*; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D009479:Neuropeptides / Q000378:metabolism; D051381:Rats; D013569:Synapses / Q000378:metabolism*; D016704:Synapsins / Q000378:metabolism; D009435:Synaptic Transmission / Q000502:physiology*; D015854:Up-Regulation / Q000502:physiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C113688:Bsn protein, rat; D003598:Cytoskeletal Proteins; C479909:ERC1 protein, rat; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; C405514:Pclo protein, rat; D016704:Synapsins; C103912:Unc13a protein, rat