Allele-dependent changes of olivocerebellar circuit properties in the absence of the voltage-gated potassium channels Kv3.1 and Kv3.3.
Double-mutant mice (DKO) lacking the two voltage-gated K(+) channels Kv3.1 and Kv3.3 display a series of phenotypic alterations that include ataxia, myoclonus, tremor and alcohol hypersensitivity. The prominent cerebellar expression of mRNAs encoding Kv3.1 and Kv3.3 subunits raised the question as to whether altered electrical activity resulting from the lack of these K(+) channels might be related to the dramatic motor changes. We used the tremorogenic agent harmaline to probe mutant mice lacking different K(+) channel alleles for altered olivocerebellar circuit properties. Harmaline induced the characteristic 13-Hz tremor in wildtype mice (WT); however, no tremor was observed in DKO suggesting that the ensemble properties of the olivocerebellar circuitry are altered in the absence of Kv3.1 and Kv3.3 subunits. Harmaline induced tremor in Kv3.1-single mutants, but it was of smaller amplitude and at a lower frequency indicating the participation of Kv3.1 subunits in normal olivocerebellar system function. In contrast, harmaline tremor was virtually absent in Kv3.3-single mutants indicating an essential role for Kv3.3 subunits in tremor induction by harmaline. Immunohistochemical staining for Kv3.3 showed clear expression in the somata and proximal dendrites of Purkinje cells and in their axonal projections to the deep cerebellar nuclei (DCN). In DCN, both Kv3.1 and Kv3.3 subunits are expressed. Action potential duration is increased by approximately 100% in Purkinje cells from Kv3.3-single mutants compared to WT or Kv3.1-single mutants. We conclude that Kv3.3 channel subunits are essential for the olivocerebellar system to generate and sustain normal harmaline tremor whereas Kv3.1 subunits influence tremor amplitude and frequency.
McMahon
Anne
A
Center for Basic Neuroscience, The University of Texas Southwestern Medical Center, Dallas, Texas 75390-9111, USA.
Fowler
Stephen C
SC
Perney
Teresa M
TM
Akemann
Walther
W
Knöpfel
Thomas
T
Joho
Rolf H
RH
D000200:Action Potentials / Q000502:physiology; D000483:Alleles; D000818:Animals; D015153:Blotting, Western; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D002531:Cerebellum / Q000187:drug effects / Q000502:physiology*; D006246:Harmaline / Q000494:pharmacology; D007150:Immunohistochemistry; D051379:Mice; D008817:Mice, Mutant Strains; D018613:Microscopy, Confocal; D009043:Motor Activity / Q000502:physiology; D009154:Mutation; D009434:Neural Pathways / Q000187:drug effects / Q000502:physiology*; D009847:Olivary Nucleus / Q000187:drug effects / Q000502:physiology*; D009924:Organ Culture Techniques; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000172:deficiency* / Q000235:genetics; D024642:Potassium Channels, Voltage-Gated; D051670:Shaw Potassium Channels; D014202:Tremor / Q000139:chemically induced / Q000235:genetics
D000697:Central Nervous System Stimulants; C490839:Kcnc1 protein, mouse; C085724:Kcnc3 protein, mouse; C484184:Kcnc3 protein, rat; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D051670:Shaw Potassium Channels; D006246:Harmaline