Purkinje-cell-restricted restoration of Kv3.3 function restores complex spikes and rescues motor coordination in Kcnc3 mutants.
The fast-activating/deactivating voltage-gated potassium channel Kv3.3 (Kcnc3) is expressed in various neuronal cell types involved in motor function, including cerebellar Purkinje cells. Spinocerebellar ataxia type 13 (SCA13) patients carrying dominant-negative mutations in Kcnc3 and Kcnc3-null mutant mice both display motor incoordination, suggested in mice by increased lateral deviation while ambulating and slips on a narrow beam. Motor skill learning, however, is spared. Mice lacking Kcnc3 also exhibit muscle twitches. In addition to broadened spikes, recordings of Kcnc3-null Purkinje cells revealed fewer spikelets in complex spikes and a lower intraburst frequency. Targeted reexpression of Kv3.3 channels exclusively in Purkinje cells in Kcnc3-null mice as well as in mice also heterozygous for Kv3.1 sufficed to restore simple spike brevity along with normal complex spikes and to rescue specifically coordination. Therefore, spike parameters requiring Kv3.3 function in Purkinje cells are involved in the ataxic null phenotype and motor coordination, but not motor learning.
Hurlock
Edward C
EC
Department of Neuroscience, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
McMahon
Anne
A
Joho
Rolf H
RH
D000200:Action Potentials / Q000235:genetics / Q000502:physiology* / Q000528:radiation effects; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal; D002531:Cerebellum / Q000166:cytology; D004307:Dose-Response Relationship, Radiation; D004558:Electric Stimulation / Q000379:methods; D005260:Female; D015870:Gene Expression / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009048:Motor Skills / Q000502:physiology*; D009154:Mutation / Q000502:physiology*; D018408:Patch-Clamp Techniques; D004856:Postural Balance / Q000502:physiology*; D011689:Purkinje Cells / Q000502:physiology*; D051670:Shaw Potassium Channels / Q000172:deficiency / Q000502:physiology*
C085724:Kcnc3 protein, mouse; D051670:Shaw Potassium Channels; D049452:Green Fluorescent Proteins