title: MSK1 regulates homeostatic and experience-dependent synaptic plasticity.
abstract: The ability of neurons to modulate synaptic strength underpins synaptic plasticity, learning and memory, and adaptation to sensory experience. Despite the importance of synaptic adaptation in directing, reinforcing, and revising the behavioral response to environmental influences, the cellular and molecular mechanisms underlying synaptic adaptation are far from clear. Brain-derived neurotrophic factor (BDNF) is a prime initiator of structural and functional synaptic adaptation. However, the signaling cascade activated by BDNF to initiate these adaptive changes has not been elucidated. We have previously shown that BDNF activates mitogen- and stress-activated kinase 1 (MSK1), which regulates gene transcription via the phosphorylation of both CREB and histone H3. Using mice with a kinase-dead knock-in mutation of MSK1, we now show that MSK1 is necessary for the upregulation of synaptic strength in response to environmental enrichment in vivo. Furthermore, neurons from MSK1 kinase-dead mice failed to show scaling of synaptic transmission in response to activity deprivation in vitro, a deficit that could be rescued by reintroduction of wild-type MSK1. We also show that MSK1 forms part of a BDNF- and MAPK-dependent signaling cascade required for homeostatic synaptic scaling, which likely resides in the ability of MSK1 to regulate cell surface GluA1 expression via the induction of Arc/Arg3.1. These results demonstrate that MSK1 is an integral part of a signaling pathway that underlies the adaptive response to synaptic and environmental experience. MSK1 may thus act as a key homeostat in the activity- and experience-dependent regulation of synaptic strength.
authors.affiliation: School of Life Sciences and Molecular Organisation and Assembly in Cells, University of Warwick, Coventry CV4 7AL, United Kingdom.
authors.forename: Sonia A L
authors.initials: SA
authors.lastname: Corrêa
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Hunter
authors.forename: Oleg
authors.initials: O
authors.lastname: Palygin
authors.forename: Sandrine C
authors.initials: SC
authors.lastname: Wauters
authors.forename: Kirsty J
authors.initials: KJ
authors.lastname: Martin
authors.forename: Colin
authors.initials: C
authors.lastname: McKenzie
authors.forename: Kim
authors.initials: K
authors.lastname: McKelvey
authors.forename: Richard G M
authors.initials: RG
authors.lastname: Morris
authors.forename: Yuriy
authors.initials: Y
authors.lastname: Pankratov
authors.forename: J Simon C
authors.initials: JS
authors.lastname: Arthur
authors.forename: Bruno G
authors.initials: BG
authors.lastname: Frenguelli
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000378:metabolism; D049229:Dendritic Spines / Q000502:physiology; D004777:Environment; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics; D006624:Hippocampus / Q000166:cytology; D006706:Homeostasis / Q000187:drug effects / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009473:Neuronal Plasticity / Q000187:drug effects / Q000235:genetics*; D009474:Neurons / Q000378:metabolism* / Q000648:ultrastructure; D018408:Patch-Clamp Techniques; D017354:Point Mutation / Q000235:genetics; D018091:Receptors, AMPA / Q000378:metabolism; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013569:Synapses / Q000235:genetics / Q000502:physiology*; D013779:Tetrodotoxin / Q000494:pharmacology; D013997:Time Factors
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D003598:Cytoskeletal Proteins; D004791:Enzyme Inhibitors; D049452:Green Fluorescent Proteins; D009419:Nerve Tissue Proteins; D018091:Receptors, AMPA; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D026941:Sodium Channel Blockers; D013779:Tetrodotoxin; C092069:activity regulated cytoskeletal-associated protein; C116919:mitogen and stress-activated protein kinase 1; C104722:glutamate receptor ionotropic, AMPA 2