| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1 Human Genetics, University of Michigan, Ann Arbor, Michigan, United States; Unit for Laboratory Animal Medicine, University of Michigan, Ann Arbor, Michigan, United States
2 Department of Neurobiology and Physiology, Northwestern University, Evanston, Illinois, United States
3 Human Genetics, University of Michigan, Ann Arbor, Michigan, United States
* To whom correspondence should be addressed. E-mail: meislerm{at}umich.edu.
The Scn8a gene encodes the voltage-gated Na channel 
subunit NaV1.6, which is widely expressed throughout the nervous system. Global null mutations that eliminate Scn8a in all cells result in severe motor dysfunction and premature death, precluding analysis of the physiological role of NaV1.6 in different neuronal types. To test the effect of cerebellar NaV1.6 on motor coordination in mice, we used the Cre-lox system to eliminate Scn8a expression exclusively in Purkinje neurons (Purkinje KO) and/or granule neurons (granule KO). While granule KO mice had only minor behavioral defects, adult Purkinje KO mice exhibited ataxia, tremor, and impaired coordination. These disorders were exacerbated in double mutants lacking Scn8a in both Purkinje and granule cells (double KO). In Purkinje cells isolated from adult Purkinje KO and double KO but not granule KO mice, the ratio of resurgent-to-transient tetrodotoxin- (TTX)-sensitive Na current amplitudes decreased from ~15% to ~5%. In cerebellar slices, Purkinje cell spontaneous and maximal firing rates were reduced 10-fold and 2-fold relative to control in Purkinje KO and double KO but not granule KO mice. Additionally, short-term plasticity of high-frequency parallel fiber EPSCs was altered relative to control in Purkinje KO and double KO but not granule KO mice. These data suggest that the specialized kinetics of Purkinje Na channels depend directly on Scn8a expression. The loss of these channels leads to a decrease in Purkinje cell firing rates as well as a modification of the synaptic properties of afferent parallel fibers, with the ultimate consequence of disrupting motor behavior.
This article has been cited by other articles:
|
|
 |
|
  W. A. Catterall, S. Dib-Hajj, M. H. Meisler, and D. Pietrobon Inherited Neuronal Ion Channelopathies: New Windows on Complex Neurological Diseases J. Neurosci., November 12, 2008; 28(46): 11768 - 11777. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Royeck, M.-T. Horstmann, S. Remy, M. Reitze, Y. Yaari, and H. Beck Role of Axonal NaV1.6 Sodium Channels in Action Potential Initiation of CA1 Pyramidal Neurons J Neurophysiol, October 1, 2008; 100(4): 2361 - 2380. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. P. Carlin, J. Liu, and L. M. Jordan Postnatal Changes in the Inactivation Properties of Voltage-Gated Sodium Channels Contribute to the Mature Firing Pattern of Spinal Motoneurons J Neurophysiol, June 1, 2008; 99(6): 2864 - 2876. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. C. Hurlock, A. McMahon, and R. H. Joho Purkinje-Cell-Restricted Restoration of Kv3.3 Function Restores Complex Spikes and Rescues Motor Coordination in Kcnc3 Mutants J. Neurosci., April 30, 2008; 28(18): 4640 - 4648. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Zeller, F. Crestani, I. Camenisch, T. Iwasato, S. Itohara, J. M. Fritschy, and U. Rudolph Cortical Glutamatergic Neurons Mediate the Motor Sedative Action of Diazepam Mol. Pharmacol., February 1, 2008; 73(2): 282 - 291. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. N. Mercer, C. S. Chan, T. Tkatch, J. Held, and D. J. Surmeier Nav1.6 Sodium Channels Are Critical to Pacemaking and Fast Spiking in Globus Pallidus Neurons J. Neurosci., December 5, 2007; 27(49): 13552 - 13566. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. S. Martin, B. Tang, L. A. Papale, F. H. Yu, W. A. Catterall, and A. Escayg The voltage-gated sodium channel Scn8a is a genetic modifier of severe myoclonic epilepsy of infancy Hum. Mol. Genet., December 1, 2007; 16(23): 2892 - 2899. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Kalume, F. H. Yu, R. E. Westenbroek, T. Scheuer, and W. A. Catterall Reduced Sodium Current in Purkinje Neurons from NaV1.1 Mutant Mice: Implications for Ataxia in Severe Myoclonic Epilepsy in Infancy J. Neurosci., October 10, 2007; 27(41): 11065 - 11074. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. G. Brickley, M. I. Aller, C. Sandu, E. L. Veale, F. G. Alder, H. Sambi, A. Mathie, and W. Wisden TASK-3 Two-Pore Domain Potassium Channels Enable Sustained High-Frequency Firing in Cerebellar Granule Neurons J. Neurosci., August 29, 2007; 27(35): 9329 - 9340. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Rosker, B. Lohberger, D. Hofer, B. Steinecker, S. Quasthoff, and W. Schreibmayer The TTX metabolite 4,9-anhydro-TTX is a highly specific blocker of the Nav1.6 voltage-dependent sodium channel Am J Physiol Cell Physiol, August 1, 2007; 293(2): C783 - C789. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. K. Aman and I. M. Raman Subunit Dependence of Na Channel Slow Inactivation and Open Channel Block in Cerebellar Neurons Biophys. J., March 15, 2007; 92(6): 1938 - 1951. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
| Visit Other APS Journals Online |
