Corrêa, Sônia A. L., Hunter, Christopher J., Palygin, Oleg, Wauters, Sandrine, Martin, Kirsty J., McKenzie, Colin, McKelvey, Kim M. (Kim Martin), Morris, R. G. M. (Richard G. M.), Pankratov, Yuriy, Arthur, J. Simon C. and Frenguelli, Bruno G. (2012) MSK1 regulates homeostatic and experience-dependent synaptic plasticity. Journal of Neuroscience, Vol.32 (No.38). pp. 13039-13051. doi:10.1523/JNEUROSCI.0930-12.2012

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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.

Item Type:	Journal Article
Subjects:	Q Science > QP Physiology
Divisions:	Faculty of Science > Life Sciences (2010- )
Library of Congress Subject Headings (LCSH):	Neuroplasticity, Mitogen-activated protein kinases, Neurons -- Physiology
Journal or Publication Title:	Journal of Neuroscience
Publisher:	Society for Neuroscience
ISSN:	0270-6474
Official Date:	19 September 2012
Dates:	Date Event 19 September 2012 Published
Date of first compliant deposit:	23 December 2015
Volume:	Vol.32
Number:	No.38
Page Range:	pp. 13039-13051
DOI:	10.1523/JNEUROSCI.0930-12.2012
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Restricted or Subscription Access
Funder:	Medical Research Council (Great Britain) (MRC), Sixth Framework Programme (European Commission) (FP6), Biotechnology and Biological Sciences Research Council (Great Britain) (BBSRC), University of Warwick, GlaxoSmithKline, Wellcome Trust (London, England), Engineering and Physical Sciences Research Council (EPSRC), University of Warwick. Molecular Organisation and Assembly in Cells

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