title: LKB1 and AMPK regulate synaptic remodeling in old age.
abstract: Age-related decreases in neural function result in part from alterations in synapses. To identify molecular defects that lead to such changes, we focused on the outer retina, in which synapses are markedly altered in old rodents and humans. We found that the serine/threonine kinase LKB1 and one of its substrates, AMPK, regulate this process. In old mice, synaptic remodeling was accompanied by specific decreases in the levels of total LKB1 and active (phosphorylated) AMPK. In the absence of either kinase, young adult mice developed retinal defects similar to those that occurred in old wild-type animals. LKB1 and AMPK function in rod photoreceptors where their loss leads to aberrant axonal retraction, the extension of postsynaptic dendrites and the formation of ectopic synapses. Conversely, increasing AMPK activity genetically or pharmacologically attenuates and may reverse age-related synaptic alterations. Together, these results identify molecular determinants of age-related synaptic remodeling and suggest strategies for attenuating these changes.
authors.affiliation: 1] Department of Molecular and Cellular Biology and Center for Brain Science, Harvard University, Cambridge, Massachusetts, USA. [2].
authors.forename: Melanie A
authors.initials: MA
authors.lastname: Samuel
authors.affiliation: 1] Department of Molecular and Cellular Biology and Center for Brain Science, Harvard University, Cambridge, Massachusetts, USA. [2].
authors.forename: P Emanuela
authors.initials: PE
authors.lastname: Voinescu
authors.affiliation: Department of Molecular and Cellular Biology and Center for Brain Science, Harvard University, Cambridge, Massachusetts, USA.
authors.forename: Brendan N
authors.initials: BN
authors.lastname: Lilley
authors.affiliation: Laboratory of Experimental Gerontology, Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, Baltimore, Maryland, USA.
authors.forename: Rafa
authors.initials: R
authors.lastname: de Cabo
authors.affiliation: 1] Inserm, U1016, Institut Cochin, Paris, France. [2] CNRS, UMR8104, Paris, France. [3] Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Foretz
authors.affiliation: 1] Inserm, U1016, Institut Cochin, Paris, France. [2] CNRS, UMR8104, Paris, France. [3] Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: Viollet
authors.affiliation: The Berman-Gund Laboratory for the Study of Retinal Degenerations, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Basil
authors.initials: B
authors.lastname: Pawlyk
authors.affiliation: The Berman-Gund Laboratory for the Study of Retinal Degenerations, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Sandberg
authors.affiliation: Retina Service, Angiogenesis Laboratory, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Demetrios G
authors.initials: DG
authors.lastname: Vavvas
authors.affiliation: Department of Molecular and Cellular Biology and Center for Brain Science, Harvard University, Cambridge, Massachusetts, USA.
authors.forename: Joshua R
authors.initials: JR
authors.lastname: Sanes
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics* / Q000378:metabolism; D000375:Aging / Q000473:pathology / Q000502:physiology*; D025042:Amacrine Cells / Q000473:pathology / Q000502:physiology; D000818:Animals; D004596:Electroretinography; D005260:Female; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D051245:Retinal Bipolar Cells / Q000473:pathology / Q000502:physiology; D012165:Retinal Ganglion Cells / Q000473:pathology / Q000502:physiology; D012374:Rod Cell Outer Segment / Q000473:pathology* / Q000502:physiology*; D013379:Substrate Specificity; D013569:Synapses / Q000473:pathology / Q000502:physiology
chemical_list: D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D055372:AMP-Activated Protein Kinases
references.citation: J Mol Cell Biol. 2011 Dec;3(6):330-40
references.pmid: 21926085
references.citation: Science. 2005 Feb 11;307(5711):929-32
references.pmid: 15705853
references.citation: Neurology. 2007 May 1;68(18):1501-8
references.pmid: 17470753
references.citation: J Neurosci. 2009 Jan 7;29(1):106-17
references.pmid: 19129389
references.citation: Hum Mol Genet. 2005 Oct 15;14(20):3035-46
references.pmid: 16155113
references.citation: Invest Ophthalmol Vis Sci. 2007 Jun;48(6):2824-30
references.pmid: 17525218
references.citation: Neuromolecular Med. 2012 Mar;14(1):1-14
references.pmid: 22367557
references.citation: Annu Rev Neurosci. 1981;4:17-42
references.pmid: 7013635
references.citation: Eur J Neurosci. 1999 Oct;11(10):3683-93
references.pmid: 10564375
references.citation: Genesis. 2000 Feb;26(2):130-2
references.pmid: 10686607
references.citation: Science. 2011 Apr 8;332(6026):247-51
references.pmid: 21436401
references.citation: Neuron. 2003 Mar 6;37(5):775-86
references.pmid: 12628168
references.citation: Nat Rev Neurosci. 2006 Jan;7(1):30-40
references.pmid: 16371948
references.citation: Cell. 2001 Apr 6;105(1):43-55
references.pmid: 11301001
references.citation: J Neurosci. 2009 Oct 14;29(41):12795-801
references.pmid: 19828791
references.citation: J Neurosci. 2011 Nov 2;31(44):16033-44
references.pmid: 22049445
references.citation: EMBO J. 2004 Feb 25;23(4):833-43
references.pmid: 14976552
references.citation: Nat Neurosci. 2001 Sep;4(9):877-86
references.pmid: 11528418
references.citation: Vis Neurosci. 2006 Jan-Feb;23(1):11-24
references.pmid: 16597347
references.citation: Proc Natl Acad Sci U S A. 2011 Apr 5;108(14):5849-54
references.pmid: 21436046
references.citation: Mol Vis. 2002 Dec 11;8:462-71
references.pmid: 12486395
references.citation: Development. 2008 Dec;135(24):4141-51
references.pmid: 19029044
references.citation: Nature. 2002 Sep 12;419(6903):162-7
references.pmid: 12226664
references.citation: J Gerontol A Biol Sci Med Sci. 1999 Nov;54(11):B492-501
references.pmid: 10619312
references.citation: Proc Natl Acad Sci U S A. 2004 Jul 20;101(29):10554-9
references.pmid: 15247428
references.citation: J Biol Chem. 2006 Sep 1;281(35):25336-43
references.pmid: 16835226
references.citation: Nature. 2012 Aug 23;488(7412):517-21
references.pmid: 22842903
references.citation: FEBS Lett. 2011 Apr 6;585(7):981-5
references.pmid: 21185289
references.citation: Genesis. 2005 Feb;41(2):73-80
references.pmid: 15682388
references.citation: Nature. 2009 Jan 8;457(7226):210-4
references.pmid: 19052547
references.citation: Nat Rev Neurosci. 2012 Mar 07;13(4):240-50
references.pmid: 22395804
references.citation: Nat Rev Mol Cell Biol. 2012 Mar 22;13(4):251-62
references.pmid: 22436748
references.citation: Nat Neurosci. 2011 Jul 10;14(8):965-72
references.pmid: 21743471
references.citation: J Biol Chem. 2005 Dec 23;280(51):42142-8
references.pmid: 16203737
references.citation: Proc Natl Acad Sci U S A. 2006 Aug 1;103(31):11677-82
references.pmid: 16857737
references.citation: J Biol Chem. 2003 Aug 1;278(31):28434-42
references.pmid: 12764152
references.citation: Annu Rev Biochem. 2006;75:137-63
references.pmid: 16756488
references.citation: Nat Genet. 1999 Sep;23(1):99-103
references.pmid: 10471508
references.citation: Dev Biol. 2004 Jul 15;271(2):388-402
references.pmid: 15223342
references.citation: Proc Natl Acad Sci U S A. 2006 Aug 8;103(32):12156-60
references.pmid: 16880381
references.citation: Mol Biol Cell. 2002 Nov;13(11):4013-28
references.pmid: 12429843
references.citation: J Neurosci. 2012 Aug 29;32(35):12192-203
references.pmid: 22933801
references.citation: J Neurosci. 2010 Aug 18;30(33):11222-31
references.pmid: 20720130
references.citation: Cell. 2010 Jul 9;142(1):9-14
references.pmid: 20603007
references.citation: Biochem Biophys Res Commun. 2011 Feb 25;405(4):667-72
references.pmid: 21281604
references.citation: Neuron. 2010 Apr 15;66(1):15-36
references.pmid: 20399726
references.citation: Eur J Neurosci. 2007 Nov;26(9):2506-15
references.pmid: 17970721
references.citation: Neurobiol Aging. 2009 May;30(5):819-28
references.pmid: 17920161
references.citation: Neuron. 2013 Jul 10;79(1):39-53
references.pmid: 23790753
references.citation: Cell. 2007 May 4;129(3):565-77
references.pmid: 17482549
references.citation: Cell Metab. 2013 Jan 8;17(1):101-12
references.pmid: 23312286
references.citation: J Comp Neurol. 2011 Jun 15;519(9):1691-711
references.pmid: 21452242
references.citation: Proc Natl Acad Sci U S A. 2011 Nov 1;108(44):18132-7
references.pmid: 22006306
references.citation: J Neurosci. 1998 Dec 1;18(23):10136-49
references.pmid: 9822767
references.citation: Cell. 2007 May 4;129(3):549-63
references.pmid: 17482548
references.citation: J Comp Neurol. 1974 May 1;155(1):1-14
references.pmid: 4836060
references.citation: Neurobiol Aging. 2003 Dec;24(8):1029-46
references.pmid: 14643375
references.citation: J Clin Invest. 2003 Jan;111(1):91-8
references.pmid: 12511592
references.citation: Nat Neurosci. 2004 Oct;7(10):1079-87
references.pmid: 15452577
references.citation: J Biol Chem. 2012 Jan 13;287(3):1612-9
references.pmid: 22074921
references.citation: Proc Natl Acad Sci U S A. 2010 Aug 17;107(33):14863-8
references.pmid: 20679195
references.citation: Science. 2005 Dec 9;310(5754):1642-6
references.pmid: 16308421