title: Alterations in cerebellar physiology are associated with a stiff-legged gait in Atcay(ji-hes) mice.
abstract: Recent evidence suggests that dystonia, a movement disorder characterized by sustained involuntary muscle contractions, can be associated with cerebellar abnormalities. The basis for how functional changes in the cerebellum can cause dystonia is poorly understood. Here we identify alterations in physiology in Atcay(ji-hes) mice which in addition to ataxia, have an abnormal gait with hind limb extension and toe walking, reminiscent of human dystonic gait. No morphological abnormalities in the brain accompany the dystonia, but partial cerebellectomy causes resolution of the stiff-legged gait, suggesting that cerebellar dysfunction contributes to the dystonic gait of Atcay(ji-hes) mice. Recordings from Purkinje and deep cerebellar nuclear (DCN) neurons in acute brain slices were used to determine the physiological correlates of dystonia in the Atcay(ji-hes) mice. Approximately 50% of cerebellar Purkinje neurons fail to display the normal repetitive firing characteristic of these cells. In addition, DCN neurons exhibit increased intrinsic firing frequencies with a subset of neurons displaying bursts of action potentials. This increased intrinsic excitability of DCN neurons is accompanied by a reduction in after-hyperpolarization currents mediated by small-conductance calcium-activated potassium (SK) channels. An activator of SK channels reduces DCN neuron firing frequency in acute cerebellar slices and improves the dystonic gait of Atcay(ji-hes) mice. These results suggest that a combination of reduced Purkinje neuron activity and increased DCN intrinsic excitability can result in a combination of ataxia and a dystonia-like gait in mice.
authors.affiliation: Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Katiuska
authors.initials: K
authors.lastname: Luna-Cancalon
authors.affiliation: Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Kristine M
authors.initials: KM
authors.lastname: Sikora
authors.affiliation: Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Samuel S
authors.initials: SS
authors.lastname: Pappas
authors.affiliation: Department of Pharmacology, University of California, Davis, CA 95616, USA.
authors.forename: Vikrant
authors.initials: V
authors.lastname: Singh
authors.affiliation: Department of Pharmacology, University of California, Davis, CA 95616, USA.
authors.forename: Heike
authors.initials: H
authors.lastname: Wulff
authors.affiliation: Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Henry L
authors.initials: HL
authors.lastname: Paulson
authors.affiliation: Molecular & Behavioral Neuroscience Institute, Departments of Psychiatry, Computational Medicine & Bioinformatics and Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Margit
authors.initials: M
authors.lastname: Burmeister
authors.affiliation: Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: vikramsh@med.umich.edu.
authors.forename: Vikram G
authors.initials: VG
authors.lastname: Shakkottai
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000818:Animals; D002529:Cerebellar Nuclei / Q000503:physiopathology*; D020821:Dystonic Disorders / Q000503:physiopathology*; D005684:Gait / Q000502:physiology*; D051379:Mice; D008817:Mice, Mutant Strains; D009043:Motor Activity / Q000502:physiology; D011689:Purkinje Cells / Q000502:physiology*
keywords: Ataxia; Cerebellum; Deep cerebellar nuclei; Dystonia; Electrophysiology; Mutant mice; Patch-clamp; Purkinje cells
references.citation: J Neurosci. 2003 Apr 1;23(7):2600-7
references.pmid: 12684445
references.citation: J Neurosci. 2002 Oct 1;22(19):8447-57
references.pmid: 12351719
references.citation: J Neurosci. 2011 Sep 7;31(36):13002-14
references.pmid: 21900579
references.citation: Brain. 1985 Jun;108 ( Pt 2):463-83
references.pmid: 4005532
references.citation: J Neurosci. 2002 Jun 1;22(11):4456-67
references.pmid: 12040053
references.citation: J Neurophysiol. 1978 May;41(3):654-76
references.pmid: 96223
references.citation: Nat Neurosci. 2012 Jan 08;15(2):284-93
references.pmid: 22231426
references.citation: Nat Neurosci. 2005 Nov;8(11):1491-3
references.pmid: 16205719
references.citation: Brain Res. 2012 Jun 29;1464:82-8
references.pmid: 22595488
references.citation: J Clin Invest. 2004 Feb;113(4):582-90
references.pmid: 14966567
references.citation: Neurobiol Dis. 2009 Jan;33(1):81-8
references.pmid: 18930825
references.citation: Nat Neurosci. 2011 Mar;14(3):357-65
references.pmid: 21297628
references.citation: J Comp Neurol. 1947 Dec;87(3):169-288
references.pmid: 20271577
references.citation: J Neurosci. 2000 Dec 15;20(24):9004-16
references.pmid: 11124976
references.citation: Nat Neurosci. 2006 Mar;9(3):389-97
references.pmid: 16474392
references.citation: Exp Brain Res. 1982;47(3):365-80
references.pmid: 6889975
references.citation: Mov Disord. 2011 Oct;26(12):2279-83
references.pmid: 21953512
references.citation: Nat Genet. 2003 Nov;35(3):264-9
references.pmid: 14556008
references.citation: Trends Neurosci. 1996 Dec;19(12):530-4
references.pmid: 8961481
references.citation: Brain Res. 1986 Jan 22;363(2):364-70
references.pmid: 2867817
references.citation: Brain Res. 1995 Oct 30;697(1-2):91-103
references.pmid: 8593599
references.citation: Neurobiol Dis. 2013 Feb;50:151-9
references.pmid: 23009754
references.citation: J Neurophysiol. 2007 Jan;97(1):901-11
references.pmid: 17093116
references.citation: Neurobiol Dis. 2011 May;42(2):202-9
references.pmid: 20965251
references.citation: J Neurophysiol. 1999 Oct;82(4):1697-709
references.pmid: 10515960
references.citation: Hum Mol Genet. 2013 Jan 15;22(2):271-83
references.pmid: 23087021
references.citation: J Neurophysiol. 2006 Aug;96(2):785-93
references.pmid: 16687615
references.citation: Nat Rev Mol Cell Biol. 2007 Nov;8(11):904-16
references.pmid: 17878917
references.citation: Mamm Genome. 1997 Feb;8(2):113-20
references.pmid: 9060410
references.citation: J Neurosci. 2003 Oct 22;23(29):9650-63
references.pmid: 14573545
references.citation: PLoS One. 2012;7(11):e50570
references.pmid: 23226316
references.citation: Neuron. 1997 Oct;19(4):881-91
references.pmid: 9354334
references.citation: J Neurosci. 2009 Jul 1;29(26):8452-61
references.pmid: 19571136
references.citation: J Neurophysiol. 1968 Sep;31(5):785-97
references.pmid: 4974877
references.citation: Mov Disord. 2013 Jun 15;28(7):944-57
references.pmid: 23893451
references.citation: Exp Neurol. 1993 Apr;120(2):302-10
references.pmid: 8491286
references.citation: Exp Brain Res. 2002 Aug;145(4):457-67
references.pmid: 12172657
references.citation: Mol Pharmacol. 1999 Jan;55(1):23-31
references.pmid: 9882694
references.citation: Genomics. 1996 Aug 1;35(3):533-8
references.pmid: 8812488
references.citation: J Neurosci. 2009 Aug 5;29(31):9740-7
references.pmid: 19657027
references.citation: Neurology. 2007 Jul 24;69(4):376-80
references.pmid: 17646630
references.citation: Adv Neurol. 1988;50:277-97
references.pmid: 2840806
references.citation: J Neurosci. 2002 Sep 1;22(17):7825-33
references.pmid: 12196606
references.citation: Brain Res Mol Brain Res. 2005 Nov 30;141(2):181-92
references.pmid: 16246457
references.citation: Mol Pharmacol. 2009 Feb;75(2):281-95
references.pmid: 18955585
references.citation: J Neurosci. 1988 Sep;8(9):3327-36
references.pmid: 3171680
references.citation: Neurol Clin. 1984 Aug;2(3):541-54
references.pmid: 6398404
references.citation: Neurobiol Dis. 2011 May;42(2):152-61
references.pmid: 21081162
references.citation: Neuroscience. 1998 Sep;86(2):533-45
references.pmid: 9881867
references.citation: Neurobiol Dis. 2013 Jan;49:200-10
references.pmid: 22850483
references.citation: J Neurosci. 2000 Apr 15;20(8):3006-16
references.pmid: 10751453
references.citation: Mov Disord. 2013 Jun 15;28(7):884-8
references.pmid: 23893444
references.citation: Front Neurol. 2013 Feb 14;4:7
references.pmid: 23420606
references.citation: Proc Natl Acad Sci U S A. 2004 Jun 22;101(25):9474-8
references.pmid: 15194823
references.citation: Mov Disord. 2013 Jun 15;28(7):982-9
references.pmid: 23893454
references.citation: Neurology. 2006 Nov 28;67(10):1769-73
references.pmid: 17130408
references.citation: J Cell Sci. 2006 Aug 15;119(Pt 16):3337-50
references.pmid: 16899818
references.citation: Ann Neurol. 1998 Sep;44(3):303-12
references.pmid: 9749595
references.citation: J Neurophysiol. 1986 Jun;55(6):1221-33
references.pmid: 3734856
references.citation: J Neurocytol. 1993 Feb;22(2):81-91
references.pmid: 8095297
references.citation: Brain. 1998 Jul;121 ( Pt 7):1195-212
references.pmid: 9679773
references.citation: J Neurophysiol. 1985 Aug;54(2):231-44
references.pmid: 3928831
references.citation: J Neurophysiol. 2009 Jan;101(1):234-45
references.pmid: 18987121
references.citation: Chem Biol. 2012 Oct 26;19(10):1340-53
references.pmid: 23102227
references.citation: Neurobiol Dis. 2011 May;42(2):185-201
references.pmid: 21303695
references.citation: PLoS One. 2008 Jul 16;3(7):e2686
references.pmid: 18628984