title: Evidence from computer simulations for alterations in the membrane biophysical properties and dendritic processing of synaptic inputs in mutant superoxide dismutase-1 motoneurons.
abstract: A critical step in improving our understanding of the development of amyotrophic lateral sclerosis (ALS) is to identify the factors contributing to the alterations in the excitability of motoneurons and assess their individual contributions. Here we investigated the early alterations in the passive electrical and morphological properties of neonatal spinal motoneurons that occur by 10 d after birth, long before disease onset. We identified some of the factors contributing to these alterations, and estimated their individual contributions. To achieve this goal, we undertook a computer simulation analysis using realistic morphologies of reconstructed wild-type (WT) and mutant superoxide dismutase-1 (mSOD1) motoneurons. Ion channel parameters of these models were then tuned to match the experimental data on electrical properties obtained from these same motoneurons. We found that the reduced excitability of mSOD1 models was accompanied with decreased specific membrane resistance by approximately 25% and efficacy of synaptic inputs (slow and fast) by 12-22%. Linearity of summation of synaptic currents was similar to WT. We also assessed the contribution of the alteration in dendritic morphology alone to this decreased excitability and found that it reduced the input resistance by 10% and the efficacy of synaptic inputs by 7-15%. Our results were also confirmed in models with dendritic active conductances. Our simulations indicated that the alteration in passive electrical properties of mSOD1 models resulted from concurrent alterations in their morphology and membrane biophysical properties, and consequently altered the motoneuronal dendritic processing of synaptic inputs. These results clarify new aspects of spinal motoneurons malfunction in ALS.
authors.affiliation: Department of Physiology, Northwestern University, Chicago, Illinois 60611, USA. s-lbasiouny@northwestern.edu
authors.forename: Sherif M
authors.initials: SM
authors.lastname: Elbasiouny
authors.forename: Julien
authors.initials: J
authors.lastname: Amendola
authors.forename: Jacques
authors.initials: J
authors.lastname: Durand
authors.forename: C J
authors.initials: CJ
authors.lastname: Heckman
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000201:enzymology / Q000235:genetics*; D003198:Computer Simulation; D003712:Dendrites / Q000201:enzymology / Q000502:physiology*; D019706:Excitatory Postsynaptic Potentials / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000166:cytology / Q000201:enzymology / Q000502:physiology*; D009154:Mutation / Q000235:genetics*; D009433:Neural Inhibition / Q000235:genetics; D013482:Superoxide Dismutase / Q000096:biosynthesis / Q000235:genetics*; D000072105:Superoxide Dismutase-1; D013569:Synapses / Q000201:enzymology / Q000235:genetics*
chemical_list: C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1
references.citation: J Neurophysiol. 2003 Aug;90(2):857-69
references.pmid: 12724367
references.citation: J Neurophysiol. 2005 Dec;94(6):3961-74
references.pmid: 16120667
references.citation: J Neurosci. 2009 Apr 22;29(16):5343-53
references.pmid: 19386931
references.citation: J Neurophysiol. 2006 Sep;96(3):1141-57
references.pmid: 16282206
references.citation: J Neurosci. 2000 Sep 1;20(17):6734-40
references.pmid: 10964980
references.citation: J Physiol. 1989 Feb;409:63-87
references.pmid: 2585300
references.citation: J Physiol. 2009 Jul 15;587(Pt 14):3561-72
references.pmid: 19491245
references.citation: J Neurosci. 2007 Nov 21;27(47):12977-88
references.pmid: 18032671
references.citation: Neural Comput. 1997 Aug 15;9(6):1179-209
references.pmid: 9248061
references.citation: J Cell Biol. 2005 May 23;169(4):561-7
references.pmid: 15911875
references.citation: J Physiol. 1988 Nov;405:345-67
references.pmid: 3267153
references.citation: J Neurophysiol. 1998 Jun;79(6):2847-56
references.pmid: 9636091
references.citation: J Physiol. 2008 Jul 15;586(14):3337-51
references.pmid: 18467368
references.citation: J Neurophysiol. 1992 Oct;68(4):1438-52
references.pmid: 1432091
references.citation: J Neurosci. 2008 Oct 22;28(43):10864-74
references.pmid: 18945894
references.citation: Eur J Neurosci. 2000 May;12(5):1635-46
references.pmid: 10792441
references.citation: J Neurophysiol. 1990 Aug;64(2):648-60
references.pmid: 2213137
references.citation: J Comp Neurol. 1998 Feb 2;391(1):64-77
references.pmid: 9527542
references.citation: J Physiol. 1990 Apr;423:47-62
references.pmid: 2388157
references.citation: Nat Neurosci. 1999 Jan;2(1):50-6
references.pmid: 10195180
references.citation: J Physiol. 2004 Jun 1;557(Pt 2):355-61
references.pmid: 15090607
references.citation: J Neurophysiol. 1983 Aug;50(2):399-412
references.pmid: 6310060
references.citation: Eur J Neurosci. 2007 Jan;25(2):451-9
references.pmid: 17284186
references.citation: Neurobiol Dis. 2007 Nov;28(2):154-64
references.pmid: 17766128
references.citation: Physiol Rev. 1992 Oct;72(4 Suppl):S159-86
references.pmid: 1438585
references.citation: Eur J Neurosci. 2000 May;12(5):1624-34
references.pmid: 10792440
references.citation: Eur J Neurosci. 2004 Nov;20(10):2822-6
references.pmid: 15548226
references.citation: J Neurophysiol. 1967 Sep;30(5):1138-68
references.pmid: 6055351
references.citation: J Neurosci. 2000 Apr 1;20(7):2534-42
references.pmid: 10729333
references.citation: Neurosci Lett. 1992 Aug 31;143(1-2):164-8
references.pmid: 1436663
references.citation: Science. 1998 Sep 18;281(5384):1851-4
references.pmid: 9743498
references.citation: J Neurophysiol. 1994 Apr;71(4):1468-79
references.pmid: 8035228
references.citation: Neuron. 2002 Sep 12;35(6):1067-83
references.pmid: 12354397
references.citation: J Neurophysiol. 2009 Dec;102(6):3627-42
references.pmid: 19828728
references.citation: Nat Neurosci. 2006 Mar;9(3):408-19
references.pmid: 16474388
references.citation: J Physiol. 2005 Mar 15;563(Pt 3):843-54
references.pmid: 15649979
references.citation: J Neurophysiol. 1988 Jul;60(1):60-85
references.pmid: 3404225
references.citation: J Neurophysiol. 2004 Jan;91(1):571-5
references.pmid: 14523070
references.citation: Neurobiol Dis. 2010 Feb;37(2):412-22
references.pmid: 19879358
references.citation: J Neurophysiol. 1992 Oct;68(4):1421-37
references.pmid: 1432090
references.citation: J Neurophysiol. 2001 Jan;85(1):43-53
references.pmid: 11152704
references.citation: Neuroscience. 1985 Jan;14(1):111-31
references.pmid: 2579350
references.citation: J Neurophysiol. 1999 May;81(5):2164-74
references.pmid: 10322057
references.citation: Eur J Neurosci. 1999 Oct;11(10):3481-7
references.pmid: 10564356
references.citation: Biophys J. 1969 Dec;9(12):1483-508
references.pmid: 5352228
references.citation: J Comp Neurol. 2008 Nov 20;511(3):329-41
references.pmid: 18803237
references.citation: Prog Brain Res. 1999;123:99-107
references.pmid: 10635707
references.citation: J Neuropathol Exp Neurol. 1998 Apr;57(4):329-33
references.pmid: 9600225
references.citation: Nat Neurosci. 2009 May;12(5):627-36
references.pmid: 19330001
references.citation: Exp Neurol. 2005 Mar;192(1):100-8
references.pmid: 15698623
references.citation: J Neurophysiol. 1988 Jul;60(1):149-66
references.pmid: 3404214
references.citation: J Physiol. 1992 Oct;456:473-90
references.pmid: 1293283
references.citation: Neuroscience. 1992;47(3):533-44
references.pmid: 1584408
references.citation: J Neurophysiol. 1992 Oct;68(4):1401-20
references.pmid: 1432089
references.citation: Neuron. 1997 Feb;18(2):327-38
references.pmid: 9052802
references.citation: J Neurol Sci. 2006 May 15;244(1-2):41-58
references.pmid: 16487542
references.citation: J Neurophysiol. 2000 Jan;83(1):483-500
references.pmid: 10634890
references.citation: J Neurophysiol. 2005 Nov;94(5):3465-78
references.pmid: 16079193