title: Functional alterations to the nigrostriatal system in mice lacking all three members of the synuclein family.
abstract: The synucleins (α, β, and γ) are highly homologous proteins thought to play a role in regulating neurotransmission and are found abundantly in presynaptic terminals. To overcome functional overlap between synuclein proteins and to understand their role in presynaptic signaling from mesostriatal dopaminergic neurons, we produced mice lacking all three members of the synuclein family. The effect on the mesostriatal system was assessed in adult (4- to 14-month-old) animals using a combination of behavioral, biochemical, histological, and electrochemical techniques. Adult triple-synuclein-null (TKO) mice displayed no overt phenotype and no change in the number of midbrain dopaminergic neurons. TKO mice were hyperactive in novel environments and exhibited elevated evoked release of dopamine in the striatum detected with fast-scan cyclic voltammetry. Elevated dopamine release was specific to the dorsal not ventral striatum and was accompanied by a decrease of dopamine tissue content. We confirmed a normal synaptic ultrastructure and a normal abundance of SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) protein complexes in the dorsal striatum. Treatment of TKO animals with drugs affecting dopamine metabolism revealed normal rate of synthesis, enhanced turnover, and reduced presynaptic striatal dopamine stores. Our data uniquely reveal the importance of the synuclein proteins in regulating neurotransmitter release from specific populations of midbrain dopamine neurons through mechanisms that differ from those reported in other neurons. The finding that the complete loss of synucleins leads to changes in dopamine handling by presynaptic terminals specifically in those regions preferentially vulnerable in Parkinson's disease may ultimately inform on the selectivity of the disease process.
authors: Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3QX, United Kingdom.
authors: Sabina
authors: S
authors: Anwar
authors: Owen
authors: O
authors: Peters
authors: Steven
authors: S
authors: Millership
authors: Natalia
authors: N
authors: Ninkina
authors: Natalie
authors: N
authors: Doig
authors: Natalie
authors: N
authors: Connor-Robson
authors: Sarah
authors: S
authors: Threlfell
authors: Gurdeep
authors: G
authors: Kooner
authors: Robert M
authors: RM
authors: Deacon
authors: David M
authors: DM
authors: Bannerman
authors: J Paul
authors: JP
authors: Bolam
authors: Sreeganga S
authors: SS
authors: Chandra
authors: Stephanie J
authors: SJ
authors: Cragg
authors: Richard
authors: R
authors: Wade-Martins
authors: Vladimir L
authors: VL
authors: Buchman
references: FASEB J. 2001 Apr;15(6):916-26
references: 11292651
references: J Neurochem. 2004 Jun;89(5):1126-36
references: 15147505
references: Cell. 2005 Nov 4;123(3):383-96
references: 16269331
references: Neurosci Lett. 2003 Apr 17;340(3):189-92
references: 12672538
references: J Neurosci. 2002 Apr 15;22(8):3090-9
references: 11943812
references: Neurotoxicology. 2002 Oct;23(4-5):457-60
references: 12428717
references: Nat Genet. 2009 Dec;41(12):1308-12
references: 19915575
references: Neurobiol Dis. 2006 Feb;21(2):431-43
references: 16230020
references: J Neurosci. 1998 Nov 15;18(22):9335-41
references: 9801372
references: Hum Genet. 2008 Aug;124(1):89-94
references: 18568448
references: Neurobiol Aging. 2010 May;31(5):796-804
references: 19097673
references: Trends Neurosci. 2010 Dec;33(12):559-68
references: 20961626
references: Biochemistry. 1998 Apr 7;37(14):4901-9
references: 9538008
references: Brain Res Rev. 2008 Aug;58(2):314-21
references: 18023878
references: Ann Neurol. 2009 May;65(5):610-4
references: 19475667
references: Proc Natl Acad Sci U S A. 2010 Nov 9;107(45):19573-8
references: 20974939
references: Neurochem Res. 2008 Jul;33(7):1401-9
references: 18357527
references: J Neurosci. 2006 Nov 15;26(46):11915-22
references: 17108165
references: Nat Rev Neurosci. 2001 Jul;2(7):492-501
references: 11433374
references: Proc Natl Acad Sci U S A. 1998 Mar 31;95(7):4029-34
references: 9520487
references: Nat Neurosci. 2004 Jun;7(6):583-4
references: 15146188
references: Brain. 2010 Jul;133(Pt 7):2032-44
references: 20534649
references: Eur J Neurosci. 2005 May;21(9):2445-58
references: 15932602
references: Neuron. 2000 Jan;25(1):239-52
references: 10707987
references: Mol Neurobiol. 2004 Jun;29(3):243-59
references: 15181237
references: Nature. 1996 Feb 15;379(6566):606-12
references: 8628395
references: Mol Cell Biol. 2003 Nov;23(22):8233-45
references: 14585981
references: EMBO J. 2004 Nov 10;23(22):4506-16
references: 15510220
references: Eur J Neurosci. 2008 Feb;27(4):947-57
references: 18333965
references: Psychopharmacology (Berl). 1976 Oct 20;50(1):1-6
references: 827755
references: J Cell Sci. 2005 Aug 1;118(Pt 15):3523-30
references: 16030137
references: J Neurosci. 2010 Jun 16;30(24):8083-95
references: 20554859
references: Nat Genet. 2009 Dec;41(12):1303-7
references: 19915576
references: J Neurosci. 2002 Oct 15;22(20):8797-807
references: 12388586
references: Neuropsychopharmacology. 2008 Aug;33(9):2158-66
references: 18033235
references: Neuron. 2010 Jan 14;65(1):66-79
references: 20152114
references: J Neurosci. 2003 May 15;23(10):4378-85
references: 12764127
references: Science. 2010 Sep 24;329(5999):1663-7
references: 20798282
references: Proc Natl Acad Sci U S A. 2004 Oct 12;101(41):14966-71
references: 15465911
references: Hum Mol Genet. 2009 May 15;18(10):1779-94
references: 19246516
references: J Neurosci. 2008 Oct 29;28(44):11221-30
references: 18971464
references: Trends Neurosci. 2007 May;30(5):194-202
references: 17408759
references: J Neurosci. 2004 Dec 8;24(49):11165-70
references: 15590933
references: Naunyn Schmiedebergs Arch Pharmacol. 1972;275(2):153-68
references: 4404948
references: Eur J Neurosci. 2008 Dec;28(12):2459-73
references: 19032594
references: Hum Genet. 2009 Jan;124(6):593-605
references: 18985386
references: Proc Natl Acad Sci U S A. 2001 Feb 13;98(4):1982-7
references: 11172062
references: J Neurosci. 2000 Nov 1;20(21):8209-17
references: 11050144
references: Neurobiol Dis. 2005 Nov;20(2):303-13
references: 16242637
references: J Neurochem. 2006 Nov;99(4):1188-96
references: 16981894