| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1 Physiology, Northwestern University, Chicago, IL, USA; Institute for Neuroscience, Northwestern University, Chicago, IL, USA
2 Medical Physiology, University of Utrecht, Utrecht, The Netherlands; Experimental Neurology, University of Utrecht, Utrecht, The Netherlands
3 Neurology, Northwestern University, Chicago, IL, USA; Institute for Neuroscience, Northwestern University, Chicago, IL, USA
4 Neurology, Northwestern University, Chicago, IL, USA
5 Experimental Neurology, University of Utrecht, Utrecht, The Netherlands
6 Physiology, Northwestern University, Chicago, IL, USA
7 Physiology, Northwestern University, Chicago, IL, USA; Physical Medicine and Rehabilitation, Northwestern University, Chicago, IL, USA; Institute for Neuroscience, Northwestern University, Chicago, IL, USA
8 Medical Physiology, University of Utrecht, Utrecht, The Netherlands; Surgery, University of Utrecht, Utrecht, The Netherlands
* To whom correspondence should be addressed. E-mail: a.b.a.kroese{at}med.uu.nl.
ALS (amyotrophic lateral sclerosis) is an adult-onset and deadly neurodegenerative disease characterized by a progressive and selective loss of motoneurons. Transgenic mice overexpressing a mutated human gene (G93A) coding for the enzyme SOD1 (Cu/Zn superoxide dismutase) develop a motoneuron disease resembling ALS in humans. In this generally accepted ALS model, we tested the electrophysiological properties of individual embryonic and neonatal spinal motoneurons in culture by measuring a wide range of electrical properties influencing motoneuron excitability during current clamp. There were no differences in the motoneuron resting potential, input conductance, action potential shape or afterhyperpolarization between G93A and control motoneurons. The relationship between the motoneuron's firing frequency and injected current (f-I relation) was altered. The slope of the f-I relation and the maximal firing rate of the G93A motoneurons were much greater than in the control motoneurons. Differences in spontaneous synaptic input were excluded as a cause of increased excitability. This finding identifies a markedly elevated intrinsic electrical excitability in cultured embryonic and neonatal mutant G93A spinal motoneurons. We conclude that the observed intrinsic motoneuron hyperexcitability is induced by the SOD1 toxic gain-of-function through an aberration in the process of action potential generation. This hyperexcitability may play a crucial role in the pathogenesis of ALS, as the motoneurons were cultured from presymptomatic mice.
This article has been cited by other articles:
|
|
 |
|
  Q. Chang and L. J. Martin Glycinergic Innervation of Motoneurons Is Deficient in Amyotrophic Lateral Sclerosis Mice: A Quantitative Confocal Analysis Am. J. Pathol., February 1, 2009; 174(2): 574 - 585. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. van Zundert, M. H. Peuscher, M. Hynynen, A. Chen, R. L. Neve, R. H. Brown Jr, M. Constantine-Paton, and M. C. Bellingham Neonatal Neuronal Circuitry Shows Hyperexcitable Disturbance in a Mouse Model of the Adult-Onset Neurodegenerative Disease Amyotrophic Lateral Sclerosis J. Neurosci., October 22, 2008; 28(43): 10864 - 10874. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Hegedus, C. T. Putman, N. Tyreman, and T. Gordon Preferential motor unit loss in the SOD1G93A transgenic mouse model of amyotrophic lateral sclerosis J. Physiol., July 15, 2008; 586(14): 3337 - 3351. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C.J. Heckman, M. Johnson, C. Mottram, and J. Schuster Persistent Inward Currents in Spinal Motoneurons and Their Influence on Human Motoneuron Firing Patterns Neuroscientist, June 1, 2008; 14(3): 264 - 275. [Abstract] [PDF]
|
|
|
|
|
|
S. K. Jankelowitz, J. Howells, and D. Burke Plasticity of inwardly rectifying conductances following a corticospinal lesion in human subjects J. Physiol., June 15, 2007; 581(3): 927 - 940. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Gonzalez-Forero, F. Portillo, L. Gomez, F. Montero, S. Kasparov, and B. Moreno-Lopez Inhibition of Resting Potassium Conductances by Long-Term Activation of the NO/cGMP/Protein Kinase G Pathway: A New Mechanism Regulating Neuronal Excitability J. Neurosci., June 6, 2007; 27(23): 6302 - 6312. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Zona, M. Pieri, and I. Carunchio Voltage-Dependent Sodium Channels in Spinal Cord Motor Neurons Display Rapid Recovery From Fast Inactivation in a Mouse Model of Amyotrophic Lateral Sclerosis J Neurophysiol, December 1, 2006; 96(6): 3314 - 3322. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. J. Harvey, Y. Li, X. Li, and D. J. Bennett Persistent Sodium Currents and Repetitive Firing in Motoneurons of the Sacrocaudal Spinal Cord of Adult Rats J Neurophysiol, September 1, 2006; 96(3): 1141 - 1157. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. J. Kuo, R. H. Lee, L. Zhang, and C. J. Heckman Essential role of the persistent sodium current in spike initiation during slowly rising inputs in mouse spinal neurones J. Physiol., August 1, 2006; 574(3): 819 - 834. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. R. Turner, A. Hammers, A. Al-Chalabi, C. E. Shaw, P. M. Andersen, D. J. Brooks, and P. N. Leigh Distinct cerebral lesions in sporadic and 'D90A' SOD1 ALS: studies with [11C]flumazenil PET Brain, June 1, 2005; 128(6): 1323 - 1329. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. J Kuo, T Siddique, R Fu, and C. J Heckman Increased persistent Na+ current and its effect on excitability in motoneurones cultured from mutant SOD1 mice J. Physiol., March 15, 2005; 563(3): 843 - 854. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
| Visit Other APS Journals Online |
