Alcohol hypersensitivity, increased locomotion, and spontaneous myoclonus in mice lacking the potassium channels Kv3.1 and Kv3.3

The Shaw-like potassium (K+) channels Kv3.1 and Kv3.3 are widely coexpresse d in distinct neuronal populations in the CNS, possibly explaining the rela tively "mild" phenotypes of the Kv3.1 and the Kv3.3 single mutant. Kv3.1-de ficient mice show increased cortical gamma- and decreased delta -oscillatio ns (Joho et al., 1997, 1999); otherwise, the Kv3.1-mutant phenotype is rela tively subtle (Ho et al., 1997; Sanchez et al., 2000). Kv3.3-deficient mice display no overt phenotype (Chan, 1997). To investigate whether Kv3.1 and Kv3.3 K+ channels are functionally redundant, we generated the Kv3.1/Kv3.3 double mutant. Kv3.1/Kv3.3-deficient mice were born at the expected Mendeli an frequencies indicating that neither Kv3.1 nor Kv3.3 K+ channels are esse ntial for embryonic development. Although there are no obvious changes in g ross brain anatomy, adult Kv3.1/Kv3.3-deficient mice display severe ataxia, tremulous movements, myoclonus, and hypersensitivity to ethanol. Mice appe ar unbalanced when moving, whereas at rest they exhibit whole-body jerks ev ery few seconds. In spite of the severe motor impairment, Kv3.1/Kv3.3-defic ient mice are hyperactive, show increased exploratory activity, and display no obvious learning or memory deficit. Myoclonus, tremor, and ethanol hype rsensitivity are only seen in the double-homozygous Kv3.1/Kv3.3-deficient m ice, whereas increased locomotor and exploratory activity are also present in double-heterozygous mice. The graded penetrance of mutant traits appears to depend on the number of null alleles, suggesting that some of the disti nct phenotypic traits visible in the absence of Kv3.1 and Kv3.3 K+ channels are unrelated and may be caused by localized dysfunction in different brai n regions.