title: Inhibitory synaptic regulation of motoneurons: a new target of disease mechanisms in amyotrophic lateral sclerosis.
abstract: Amyotrophic lateral sclerosis (ALS) is the third most common adult-onset neurodegenerative disease. It causes the degeneration of motoneurons and is fatal due to paralysis, particularly of respiratory muscles. ALS can be inherited, and specific disease-causing genes have been identified, but the mechanisms causing motoneuron death in ALS are not understood. No effective treatments exist for ALS. One well-studied theory of ALS pathogenesis involves faulty RNA editing and abnormal activation of specific glutamate receptors as well as failure of glutamate transport resulting in glutamate excitotoxicity; however, the excitotoxicity theory is challenged by the inability of anti-glutamate drugs to have major disease-modifying effects clinically. Nevertheless, hyperexcitability of upper and lower motoneurons is a feature of human ALS and transgenic (tg) mouse models of ALS. Motoneuron excitability is strongly modulated by synaptic inhibition mediated by presynaptic glycinergic and GABAergic innervations and postsynaptic glycine receptors (GlyR) and GABA(A) receptors; yet, the integrity of inhibitory systems regulating motoneurons has been understudied in experimental models, despite findings in human ALS suggesting that they may be affected. We have found in tg mice expressing a mutant form of human superoxide dismutase-1 (hSOD1) with a Gly93 → Ala substitution (G93A-hSOD1), causing familial ALS, that subsets of spinal interneurons degenerate. Inhibitory glycinergic innervation of spinal motoneurons becomes deficient before motoneuron degeneration is evident in G93A-hSOD1 mice. Motoneurons in these ALS mice also have insufficient synaptic inhibition as reflected by smaller GlyR currents, smaller GlyR clusters on their plasma membrane, and lower expression of GlyR1α mRNA compared to wild-type motoneurons. In contrast, GABAergic innervation of ALS mouse motoneurons and GABA(A) receptor function appear normal. Abnormal synaptic inhibition resulting from dysfunction of interneurons and motoneuron GlyRs is a new direction for unveiling mechanisms of ALS pathogenesis that could be relevant to new therapies for ALS.
authors.affiliation: Department of Pathology, Division of Neuropathology, Johns Hopkins University School of Medicine, 558 Ross Building, 720 Rutland Avenue, Baltimore, MD 21205-2196, USA. martinl@jhmi.edu
authors.forename: Lee J
authors.initials: LJ
authors.lastname: Martin
authors.forename: Qing
authors.initials: Q
authors.lastname: Chang
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology*; D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008959:Models, Neurological; D009046:Motor Neurons / Q000502:physiology*; D009433:Neural Inhibition / Q000235:genetics* / Q000502:physiology; D018079:Receptors, GABA / Q000502:physiology; D018009:Receptors, Glycine / Q000172:deficiency / Q000235:genetics; D013482:Superoxide Dismutase / Q000172:deficiency / Q000235:genetics; D000072105:Superoxide Dismutase-1; D009435:Synaptic Transmission / Q000235:genetics*
chemical_list: D018079:Receptors, GABA; D018009:Receptors, Glycine; C000606290:SOD1 protein, human; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1
references.citation: J Neurosci. 2004 Mar 3;24(9):2322-7
references.pmid: 14999083
references.citation: Exp Neurol. 2009 Jan;215(1):77-86
references.pmid: 18926824
references.citation: Neuroscience. 2003;122(1):47-58
references.pmid: 14596848
references.citation: N Engl J Med. 1992 May 28;326(22):1464-8
references.pmid: 1349424
references.citation: Ann Neurol. 1983 Jul;14(1):8-16
references.pmid: 6137185
references.citation: J Neuropathol Exp Neurol. 1999 May;58(5):459-71
references.pmid: 10331434
references.citation: J Neurochem. 2007 Sep;102(6):2008-2019
references.pmid: 17555556
references.citation: Neurology. 1997 Nov;49(5):1292-8
references.pmid: 9371911
references.citation: Neurobiol Dis. 2006 Feb;21(2):291-304
references.pmid: 16182553
references.citation: J Neuropathol Exp Neurol. 2007 Nov;66(11):1002-18
references.pmid: 17984682
references.citation: J Pharmacol Sci. 2010;112(3):352-60
references.pmid: 20173309
references.citation: Science. 2000 Jan 14;287(5451):244-6
references.pmid: 10660424
references.citation: J Neurosci Methods. 1992 Aug;44(1):59-70
references.pmid: 1434751
references.citation: Neuropharmacology. 2009 Jan;56(1):303-9
references.pmid: 18721822
references.citation: Science. 1994 Dec 9;266(5191):1709-13
references.pmid: 7992055
references.citation: Neurology. 1994 Nov;44(11):2148-53
references.pmid: 7969975
references.citation: Antioxid Redox Signal. 2009 Jul;11(7):1627-39
references.pmid: 19309264
references.citation: J Comp Neurol. 2007 Jan 1;500(1):20-46
references.pmid: 17099894
references.citation: Cell. 2002 Aug 9;110(3):385-97
references.pmid: 12176325
references.citation: Eur J Neurosci. 2008 Oct;28(7):1275-85
references.pmid: 18973555
references.citation: Respir Physiol Neurobiol. 2011 Oct 15;179(1):71-9
references.pmid: 21376841
references.citation: Curr Opin Neurobiol. 1995 Jun;5(3):318-23
references.pmid: 7580154
references.citation: Brain Res Bull. 2001 Apr;54(6):669-74
references.pmid: 11403994
references.citation: J Neurol Sci. 2000 Nov 1;180(1-2):46-51
references.pmid: 11090863
references.citation: Ann Neurol. 2007 Dec;62(6):553-9
references.pmid: 18074357
references.citation: Proc Natl Acad Sci U S A. 2005 Apr 19;102(16):5826-31
references.pmid: 15827116
references.citation: J Biol Chem. 1994 Jan 28;269(4):2607-12
references.pmid: 7507926
references.citation: Neurosci Lett. 2003 Nov 20;351(3):153-6
references.pmid: 14623129
references.citation: J Physiol. 1976 Jun;258(1):227-42
references.pmid: 940060
references.citation: Science. 2009 Feb 27;323(5918):1208-1211
references.pmid: 19251628
references.citation: Brain Pathol. 2011 Jan;21(1):1-15
references.pmid: 20653686
references.citation: Neurobiol Dis. 2005 Oct;20(1):131-40
references.pmid: 16137574
references.citation: J Neurosci. 1982 Aug;2(8):1052-61
references.pmid: 7050310
references.citation: Amyotroph Lateral Scler Other Motor Neuron Disord. 2000 Mar;1 Suppl 1:S47-51
references.pmid: 11464926
references.citation: Neuropathology. 2010 Apr;30(2):182-8
references.pmid: 20102521
references.citation: J Neurophysiol. 2006 Dec;96(6):3314-22
references.pmid: 16899637
references.citation: J Neurophysiol. 1946 May;9:191-204
references.pmid: 21028162
references.citation: J Neurosci. 2000 Jan 15;20(2):660-5
references.pmid: 10632595
references.citation: IDrugs. 2010 Aug;13(8):568-80
references.pmid: 20721828
references.citation: J Neurosci. 2008 Oct 22;28(43):10864-74
references.pmid: 18945894
references.citation: Brain. 1986 Oct;109 ( Pt 5):939-52
references.pmid: 3779374
references.citation: Ann Neurol. 1990 Jul;28(1):3-8
references.pmid: 1973889
references.citation: Neuropathology. 2007 Apr;27(2):121-6
references.pmid: 17494512
references.citation: J Comp Neurol. 1998 Feb 2;391(1):64-77
references.pmid: 9527542
references.citation: Neuron. 2003 Nov 13;40(4):797-806
references.pmid: 14622583
references.citation: Muscle Nerve. 2002 Oct;26(4):438-58
references.pmid: 12362409
references.citation: Neuroreport. 1998 Aug 3;9(11):2657-61
references.pmid: 9721951
references.citation: Am J Pathol. 2009 Feb;174(2):574-85
references.pmid: 19116365
references.citation: EMBO J. 1991 Sep;10(9):2401-9
references.pmid: 1651228
references.citation: Brain. 2003 Nov;126(Pt 11):2558-66
references.pmid: 12937082
references.citation: Science. 1994 Jun 17;264(5166):1772-5
references.pmid: 8209258
references.citation: J Neurochem. 1995 Mar;64(3):1026-33
references.pmid: 7861131
references.citation: Proc Natl Acad Sci U S A. 1994 Aug 16;91(17):8292-6
references.pmid: 8058797
references.citation: Nature. 1993 Mar 4;362(6415):59-62
references.pmid: 8446170
references.citation: Nat Genet. 2008 May;40(5):572-4
references.pmid: 18372902
references.citation: J Neurosci. 2009 Dec 2;29(48):15031-8
references.pmid: 19955354
references.citation: Neuroreport. 2004 Nov 15;15(16):2477-80
references.pmid: 15538178
references.citation: Nature. 1983 Oct 27-Nov 2;305(5937):805-8
references.pmid: 6314144
references.citation: Acta Neuropathol. 2008 Jan;115(1):97-114
references.pmid: 18026741
references.citation: Nat Rev Neurosci. 2009 Jul;10(7):507-18
references.pmid: 19543221
references.citation: Neuron. 1992 Jan;8(1):189-98
references.pmid: 1370372
references.citation: Exp Neurol. 2010 Nov;226(1):218-30
references.pmid: 20832409
references.citation: Ann Neurol. 1995 Jul;38(1):73-84
references.pmid: 7611729
references.citation: Science. 1993 Aug 20;261(5124):1047-51
references.pmid: 8351519
references.citation: N Engl J Med. 2001 May 31;344(22):1688-700
references.pmid: 11386269
references.citation: Neuron. 1999 Aug;23(4):659-74
references.pmid: 10482234
references.citation: Neuron. 1999 Aug;23(4):675-87
references.pmid: 10482235
references.citation: Neurosci Res. 2006 Jan;54(1):11-4
references.pmid: 16225946
references.citation: Eur J Neurosci. 2007 Jan;25(2):451-9
references.pmid: 17284186
references.citation: J Neuropathol Exp Neurol. 2003 Oct;62(10):1041-51
references.pmid: 14575239
references.citation: Proc Natl Acad Sci U S A. 1996 Jun 11;93(12):5709-14
references.pmid: 8650157
references.citation: Physiol Rev. 2000 Apr;80(2):767-852
references.pmid: 10747207
references.citation: Neural Plast. 2011;2011:905624
references.pmid: 21785735
references.citation: Ann Neurol. 1981 Mar;9(3):292-4
references.pmid: 6261674
references.citation: Respir Physiol Neurobiol. 2011 Oct 15;179(1):3-13
references.pmid: 21782981
references.citation: Nature. 1964 Dec 19;204:1214-5
references.pmid: 14264395
references.citation: J Neurosci. 1981 Feb;1(2):204-17
references.pmid: 7264717
references.citation: Free Radic Biol Med. 2003 Jun 1;34(11):1383-9
references.pmid: 12757848
references.citation: Neuroreport. 2005 Aug 1;16(11):1227-31
references.pmid: 16012354
references.citation: Channels (Austin). 2011 Jul-Aug;5(4):299-303
references.pmid: 21558795
references.citation: Genes Brain Behav. 2008 Jun;7(4):427-34
references.pmid: 18081837
references.citation: Cell Mol Life Sci. 2001 May;58(5-6):760-93
references.pmid: 11437237
references.citation: J Physiol. 2007 Oct 1;584(Pt 1):31-45
references.pmid: 17640932
references.citation: J Neurosci. 2001 May 15;21(10):3369-74
references.pmid: 11331366
references.citation: Pharmaceuticals (Basel). 2010;3(4):839-915
references.pmid: 21258649
references.citation: J Neurophysiol. 2009 Dec;102(6):3627-42
references.pmid: 19828728
references.citation: J Neurochem. 1996 Sep;67(3):1208-16
references.pmid: 8752128
references.citation: J Neurol Neurosurg Psychiatry. 1991 Nov;54(11):984-8
references.pmid: 1686899
references.citation: Science. 2003 Oct 3;302(5642):113-7
references.pmid: 14526083
references.citation: J Neurosci. 2010 Sep 8;30(36):11917-25
references.pmid: 20826656
references.citation: J Physiol. 2005 Mar 15;563(Pt 3):843-54
references.pmid: 15649979
references.citation: Science. 1991 May 10;252(5007):851-3
references.pmid: 1709304
references.citation: Neuropathol Appl Neurobiol. 2001 Aug;27(4):257-74
references.pmid: 11532157
references.citation: J Neurosci. 2006 Dec 20;26(51):13297-310
references.pmid: 17182780
references.citation: Science. 1999 Dec 24;286(5449):2498-500
references.pmid: 10617463
references.citation: Neuropsychiatr Dis Treat. 2009;5:577-95
references.pmid: 19966906
references.citation: Neuroscience. 2006;138(4):1179-94
references.pmid: 16442737
references.citation: Prog Neurobiol. 2008 May;85(1):94-134
references.pmid: 18282652
references.citation: Ann Neurol. 1997 Sep;42(3):335-48
references.pmid: 9307255
references.citation: J Neurophysiol. 2004 Jan;91(1):571-5
references.pmid: 14523070
references.citation: Nature. 2004 Feb 26;427(6977):801
references.pmid: 14985749
references.citation: Muscle Nerve. 2010 Apr;41(4):441-3
references.pmid: 20082418
references.citation: J Comp Neurol. 2005 Dec 12;493(2):177-92
references.pmid: 16255029
references.citation: J Physiol. 1954 Dec 10;126(3):524-62
references.pmid: 13222354
references.citation: Hum Mol Genet. 2004 Oct 1;13(19):2183-96
references.pmid: 15294873
references.citation: Neuroscience. 1995 Jan;64(2):525-35
references.pmid: 7700536
references.citation: J Biol Chem. 1982 Aug 25;257(16):9389-93
references.pmid: 6286620
references.citation: Science. 2006 Jun 2;312(5778):1389-92
references.pmid: 16741123
references.citation: Proc Natl Acad Sci U S A. 2006 Oct 24;103(43):16021-6
references.pmid: 17043238
references.citation: Eur J Neurosci. 2009 Feb;29(3):551-61
references.pmid: 19187267
references.citation: J Neurosci. 2008 Jul 16;28(29):7412-25
references.pmid: 18632945
references.citation: Curr Drug Targets CNS Neurol Disord. 2005 Apr;4(2):211-20
references.pmid: 15857305
references.citation: Exp Neurol. 2009 Feb;215(2):368-79
references.pmid: 19071115
references.citation: Acta Neuropathol. 1989;77(4):343-9
references.pmid: 2711828
references.citation: J Neurosci. 1986 Nov;6(11):3265-74
references.pmid: 3772431
references.citation: Acta Neurol Scand. 1999 Jul;100(1):6-11
references.pmid: 10416506
references.citation: Nat Neurosci. 2007 May;10(5):615-22
references.pmid: 17435755
references.citation: J Neurophysiol. 2002 Sep;88(3):1279-87
references.pmid: 12205149
references.citation: Toxicol Pathol. 2011 Jan;39(1):220-33
references.pmid: 21378209
references.citation: Proc Natl Acad Sci U S A. 1995 Oct 24;92(22):10079-83
references.pmid: 7479730
references.citation: Neurosci Lett. 1992 Apr 13;138(1):173-8
references.pmid: 1328956
references.citation: Proc Natl Acad Sci U S A. 2008 Feb 12;105(6):2052-7
references.pmid: 18250315
references.citation: J Comp Neurol. 2005 Feb 7;482(2):123-41
references.pmid: 15611994
references.citation: J Neurosci. 2008 Feb 27;28(9):2075-88
references.pmid: 18305242
references.citation: J Neurosci. 2011 Feb 23;31(8):2815-27
references.pmid: 21414903
references.citation: Hum Mol Genet. 2010 Jun 1;19(11):2284-302
references.pmid: 20223753
references.citation: J Neurophysiol. 2007 May;97(5):3607-20
references.pmid: 17344372
references.citation: Neuroscience. 2003;122(2):391-405
references.pmid: 14614905
references.citation: J Biol Chem. 2004 Apr 9;279(15):15499-504
references.pmid: 14734542
references.citation: J Clin Neurosci. 2009 Apr;16(4):505-12
references.pmid: 19231200
references.citation: Biomembranes. 1975;7:99-166
references.pmid: 1092381
references.citation: Dev Biol. 1999 Apr 1;208(1):93-109
references.pmid: 10075844
references.citation: Dev Biol. 1998 May 15;197(2):234-47
references.pmid: 9630749
references.citation: Neurobiol Dis. 2008 Mar;29(3):400-8
references.pmid: 18054242
references.citation: Hum Mol Genet. 2007 Oct 15;16 Spec No. 2:R233-42
references.pmid: 17911166
references.citation: Nature. 2010 May 13;465(7295):223-6
references.pmid: 20428114
references.citation: Physiol Rev. 2007 Jan;87(1):315-424
references.pmid: 17237348
references.citation: J Neurosci. 2002 Jun 15;22(12):4825-32
references.pmid: 12077179
references.citation: Neuroreport. 1995 Apr 19;6(6):945-8
references.pmid: 7612889
references.citation: Brain. 2004 Jun;127(Pt 6):1237-51
references.pmid: 15130949
references.citation: J Neurophysiol. 2011 Feb;105(2):806-26
references.pmid: 21106900
references.citation: Brain Res Mol Brain Res. 1997 Oct 3;49(1-2):63-70
references.pmid: 9387864
references.citation: J Neurosci. 2008 Oct 8;28(41):10234-44
references.pmid: 18842883
references.citation: Annu Rev Biochem. 1995;64:97-112
references.pmid: 7574505
references.citation: Am J Hum Genet. 2009 Jan;84(1):85-8
references.pmid: 19118816
references.citation: Eur J Neurosci. 2006 Jun;23(12):3161-70
references.pmid: 16820006
references.citation: Muscle Nerve. 1997 Jan;20(1):65-71
references.pmid: 8995585
references.citation: Endocrinology. 2005 Oct;146(10):4302-11
references.pmid: 15976053
references.citation: Dev Biol. 1984 Nov;106(1):194-210
references.pmid: 6489607
references.citation: Eur J Neurosci. 1992;4(5):389-395
references.pmid: 12106346
references.citation: Chem Biodivers. 2010 Jun;7(6):1479-90
references.pmid: 20564566
references.citation: Exp Neurol. 2009 Aug;218(2):333-46
references.pmid: 19272377
references.citation: J Neurosci. 1993 Jul;13(7):2749-57
references.pmid: 7687278
references.citation: J Neurochem. 2007 Jul;102(1):170-8
references.pmid: 17394546
references.citation: J Neurosci. 1987 Oct;7(10):3088-104
references.pmid: 2822863
references.citation: J Neurol Sci. 2006 May 15;244(1-2):41-58
references.pmid: 16487542
references.citation: Brain Res. 2006 Apr 14;1083(1):196-203
references.pmid: 16546142
references.citation: Eur J Neurosci. 2009 Dec;30(11):2100-11
references.pmid: 19930400