title: Differential role of the proteasome in the early and late phases of BDNF-induced facilitation of LTP.
abstract: The neurotrophin brain-derived neurotrophic factor (BDNF) mediates activity-dependent long-term changes of synaptic strength in the CNS. The effects of BDNF are partly mediated by stimulation of local translation, with consequent alterations in the synaptic proteome. The ubiquitin-proteasome system (UPS) also plays an important role in protein homeostasis at the synapse by regulating synaptic activity. However, whether BDNF acts on the UPS to mediate the effects on long-term synaptic potentiation (LTP) has not been investigated. In the present study, we show similar and nonadditive effects of BDNF and proteasome inhibition on the early phase of synaptic potentiation (E-LTP) induced by theta-burst stimulation of rat hippocampal CA1 synapses. The effects of BDNF were blocked by the proteasome activator IU1, suggesting that the neurotrophin acts by decreasing proteasome activity. Accordingly, BDNF downregulated the proteasome activity in cultured hippocampal neurons and in hippocampal synaptoneurosomes. Furthermore, BDNF increased the activity of the deubiquitinating enzyme UchL1 in synaptoneurosomes and upregulated free ubiquitin. In contrast to the effects on posttetanic potentiation, proteasome activity was required for BDNF-mediated LTP. These results show a novel role for BDNF in UPS regulation at the synapse, which is likely to act together with the increased translation activity in the regulation of the synaptic proteome during E-LTP.
authors.affiliation: Center for Neuroscience and Cell Biology.
authors.forename: Ana Rita
authors.identifier: http://orcid.org/0000-0003-1603-6721
authors.initials: AR
authors.lastname: Santos
authors.affiliation: Center for Neuroscience and Cell Biology, Institute for Interdisciplinary Research, and.
authors.forename: Miranda
authors.initials: M
authors.lastname: Mele
authors.affiliation: Institute of Pharmacology and Neurosciences, Faculty of Medicine, and Unit of Neurosciences, Institute of Molecular Medicine, University of Lisbon, 1649-028 Lisbon, Portugal.
authors.forename: Sandra H
authors.initials: SH
authors.lastname: Vaz
authors.affiliation: Center for Neuroscience and Cell Biology.
authors.forename: Blanka
authors.initials: B
authors.lastname: Kellermayer
authors.affiliation: Center for Neuroscience and Cell Biology.
authors.forename: Maddalena
authors.identifier: http://orcid.org/0000-0002-9254-1183
authors.initials: M
authors.lastname: Grimaldi
authors.affiliation: Institute of Pharmacology and Neurosciences, Faculty of Medicine, and Unit of Neurosciences, Institute of Molecular Medicine, University of Lisbon, 1649-028 Lisbon, Portugal.
authors.forename: Mariana
authors.initials: M
authors.lastname: Colino-Oliveira
authors.affiliation: Institute of Pharmacology and Neurosciences, Faculty of Medicine, and Unit of Neurosciences, Institute of Molecular Medicine, University of Lisbon, 1649-028 Lisbon, Portugal.
authors.forename: Diogo M
authors.identifier: http://orcid.org/0000-0002-9922-7381
authors.initials: DM
authors.lastname: Rombo
authors.affiliation: Center for Neuroscience and Cell Biology.
authors.forename: Diogo
authors.initials: D
authors.lastname: Comprido
authors.affiliation: Institute of Pharmacology and Neurosciences, Faculty of Medicine, and Unit of Neurosciences, Institute of Molecular Medicine, University of Lisbon, 1649-028 Lisbon, Portugal.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Sebastião
authors.affiliation: Center for Neuroscience and Cell Biology, Department of Life Sciences, University of Coimbra, 3004-504 Coimbra, Portugal, and cbduarte@ci.uc.pt.
authors.forename: Carlos B
authors.initials: CB
authors.lastname: Duarte
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology*; D056547:CA1 Region, Hippocampal / Q000378:metabolism* / Q000502:physiology; D002478:Cells, Cultured; D017774:Long-Term Potentiation; D008297:Male; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects / Q000378:metabolism*; D011758:Pyrroles / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D013826:Theta Rhythm; D025801:Ubiquitin / Q000378:metabolism; D043222:Ubiquitin Thiolesterase / Q000378:metabolism
chemical_list: C000594744:1-(1-(4-fluorophenyl)-2,5-dimethylpyrrol-3-yl)-2-pyrrolidin-1-ylethanone; D019208:Brain-Derived Neurotrophic Factor; D011758:Pyrroles; D011759:Pyrrolidines; D025801:Ubiquitin; C489034:UCHL1 protein, rat; D043222:Ubiquitin Thiolesterase; D046988:Proteasome Endopeptidase Complex
keywords: BDNF; LTP; deubiquitinating enzymes; proteasome; synaptic plasticity