title: ADAR-mediated RNA editing suppresses sleep by acting as a brake on glutamatergic synaptic plasticity.
abstract: It has been postulated that synaptic potentiation during waking is offset by a homoeostatic reduction in net synaptic strength during sleep. However, molecular mechanisms to support such a process are lacking. Here we demonstrate that deficiencies in the RNA-editing gene Adar increase sleep due to synaptic dysfunction in glutamatergic neurons in Drosophila. Specifically, the vesicular glutamate transporter is upregulated, leading to over-activation of NMDA receptors, and the reserve pool of glutamatergic synaptic vesicles is selectively expanded in Adar mutants. Collectively these changes lead to sustained neurotransmitter release under conditions that would otherwise result in synaptic depression. We propose that a shift in the balance from synaptic depression towards synaptic potentiation in sleep-promoting neurons underlies the increased sleep pressure of Adar-deficient animals. Our findings provide a plausible molecular mechanism linking sleep and synaptic plasticity.
authors.affiliation: Department of Pharmacology, University of California San Diego, La Jolla, California 92093-0636, USA.|Biomedical Sciences Graduate Program and Molecular Pharmacology Training Grant, University of California San Diego, La Jolla, California 92093-0636, USA.
authors.forename: J E
authors.initials: JE
authors.lastname: Robinson
authors.affiliation: Department of Neurobiology, University of Southern California, Los Angeles, California 90089-2520, USA.
authors.forename: J
authors.initials: J
authors.lastname: Paluch
authors.affiliation: Department of Neurobiology, University of Southern California, Los Angeles, California 90089-2520, USA.
authors.forename: D K
authors.initials: DK
authors.lastname: Dickman
authors.affiliation: Department of Pharmacology, University of California San Diego, La Jolla, California 92093-0636, USA.|Biomedical Sciences Graduate Program and Molecular Pharmacology Training Grant, University of California San Diego, La Jolla, California 92093-0636, USA.|Neurosciences Graduate Program, University of California San Diego, La Jolla, California 92093-0636, USA.|Center for Circadian Biology, University of California San Diego, La Jolla, California 92093-0636, USA.
authors.forename: W J
authors.initials: WJ
authors.lastname: Joiner
mesh_terms: D000243:Adenosine Deaminase / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D004330:Drosophila / Q000201:enzymology* / Q000235:genetics / Q000502:physiology*; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism*; D008297:Male; D009473:Neuronal Plasticity; D009474:Neurons / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000378:metabolism; D017393:RNA Editing; D012890:Sleep; D013572:Synaptic Vesicles / Q000378:metabolism
chemical_list: D029721:Drosophila Proteins; D018377:Neurotransmitter Agents; D018698:Glutamic Acid; C567956:Adar protein, Drosophila; D000243:Adenosine Deaminase
references.citation: J Clin Invest. 2001 Mar;107(6):685-93
references.pmid: 11254668
references.citation: J Neurosci. 2008 Sep 17;28(38):9377-85
references.pmid: 18799671
references.citation: Arch Intern Med. 2003 Jan 27;163(2):205-9
references.pmid: 12546611
references.citation: Nature. 2004 Feb 26;427(6977):801
references.pmid: 14985749
references.citation: Science. 2004 May 14;304(5673):1021-4
references.pmid: 15143284
references.citation: Eur J Neurosci. 2004 Aug;20(3):611-22
references.pmid: 15255973
references.citation: Neuron. 1992 Jan;8(1):189-98
references.pmid: 1370372
references.citation: Development. 1993 Jun;118(2):401-15
references.pmid: 8223268
references.citation: Science. 1994 Dec 9;266(5191):1709-13
references.pmid: 7992055
references.citation: Cell. 1996 Dec 27;87(7):1327-38
references.pmid: 8980238
references.citation: J Neurosci. 1997 Jan 1;17(1):58-69
references.pmid: 8987736
references.citation: Neuron. 1998 May;20(5):917-25
references.pmid: 9620696
references.citation: J Physiol. 1955 Oct 28;130(1):114-22
references.pmid: 13278890
references.citation: J Neurosci. 2004 Nov 17;24(46):10466-74
references.pmid: 15548661
references.citation: Arch Intern Med. 2005 Apr 25;165(8):863-7
references.pmid: 15851636
references.citation: Curr Biol. 2005 Jul 12;15(13):1165-75
references.pmid: 16005288
references.citation: J Neurosci. 2005 Aug 10;25(32):7377-84
references.pmid: 16093388
references.citation: Neuron. 2005 Sep 15;47(6):859-72
references.pmid: 16157280
references.citation: J Neurosci. 2006 Jan 25;26(4):1239-46
references.pmid: 16436611
references.citation: Hypertension. 2006 May;47(5):833-9
references.pmid: 16585410
references.citation: Curr Biol. 2006 Jun 6;16(11):1051-62
references.pmid: 16753559
references.citation: Nature. 2006 Jun 8;441(7094):753-6
references.pmid: 16760979
references.citation: Nature. 2006 Jun 8;441(7094):757-60
references.pmid: 16760980
references.citation: Prog Cardiovasc Dis. 2009 Jan-Feb;51(4):294-302
references.pmid: 19110131
references.citation: J Neurosci. 2009 Feb 18;29(7):1948-61
references.pmid: 19228950
references.citation: Genetics. 2009 Aug;182(4):1089-100
references.pmid: 19487563
references.citation: Science. 2009 Nov 20;326(5956):1127-30
references.pmid: 19965435
references.citation: Neuron. 2010 Mar 11;65(5):670-81
references.pmid: 20223202
references.citation: J Neurosci. 2010 Sep 8;30(36):11917-25
references.pmid: 20826656
references.citation: J Vis Exp. 2011;(48). pii: 2541. doi: 10.3791/2541
references.pmid: 21372791
references.citation: J Biol Chem. 2011 Mar 11;286(10):8325-37
references.pmid: 21078670
references.citation: Nature. 2011 Mar 24;471(7339):473-9
references.pmid: 21179090
references.citation: Nat Methods. 2011 May;8(5):405-7
references.pmid: 21460824
references.citation: Cell. 2011 Jul 22;146(2):194-207
references.pmid: 21784243
references.citation: J Neurosci. 2011 Jul 27;31(30):10971-82
references.pmid: 21795546
references.citation: J Neurosci. 2011 Sep 7;31(36):12759-66
references.pmid: 21900555
references.citation: J Neurosci. 2011 Sep 14;31(37):13137-46
references.pmid: 21917797
references.citation: J Neurosci. 2011 Oct 12;31(41):14800-9
references.pmid: 21994397
references.citation: Neural Plast. 2012;2012:264378
references.pmid: 22530156
references.citation: Nat Methods. 2012 Jul;9(7):676-82
references.pmid: 22743772
references.citation: Cell Rep. 2012 Oct 25;2(4):991-1001
references.pmid: 23063364
references.citation: Mol Cell Neurosci. 2013 Jan;52:173-80
references.pmid: 23127996
references.citation: J Neurosci. 2013 Jul 3;33(27):10938-49
references.pmid: 23825400
references.citation: Nat Commun. 2013;4:2392
references.pmid: 23999086
references.citation: EMBO Mol Med. 2013 Nov;5(11):1710-9
references.pmid: 24115583
references.citation: Nat Struct Mol Biol. 2013 Nov;20(11):1333-9
references.pmid: 24077224
references.citation: Neuron. 2014 Jan 8;81(1):12-34
references.pmid: 24411729
references.citation: Elife. 2014;3:e01473
references.pmid: 24497543
references.citation: Curr Biol. 2014 Mar 17;24(6):621-9
references.pmid: 24613312
references.citation: PLoS One. 2015;10(5):e0128101
references.pmid: 26023770
references.citation: Neurobiol Learn Mem. 2011 Nov;96(4):564-82
references.pmid: 21875679
references.citation: Neuron. 2006 Jan 5;49(1):11-6
references.pmid: 16387635
references.citation: J Neurosci. 2006 Jan 11;26(2):479-89
references.pmid: 16407545
references.citation: J Psychiatr Res. 2006 Dec;40(8):700-8
references.pmid: 16978649
references.citation: Brain Res. 2007 Oct 31;1178:52-64
references.pmid: 17904536
references.citation: Sleep. 2007 Dec;30(12):1667-73
references.pmid: 18246976
references.citation: Neuroscience. 2008 Jun 23;154(2):821-31
references.pmid: 18495360
references.citation: Nat Genet. 2002 Oct;32(2):290-5
references.pmid: 12244319