Severe Motor Impairment in Kv3 Channel-deficient Mice

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Voltage-gated potassium (K+) channels form a large family of ion channels that are involved in establishing the resting membrane potential, in determining the action potential waveform and duration, in regulating release of neurotransmitter, and in modulating rhythmic firing patterns and pacemaker activity of neurons. The pivotal importance of K+ channels is underlined by several inherited human disorders in which some of these channels are dysfunctional. The two voltage-gated K+ channels Kv3.1 and Kv3.3 have unique biophysical properties and are extensively co-expressed throughout the nervous system. When individually knocked out in mice, each mutant displays only a subtle (Kv3.1) or no overt (Kv3.3) phenotype. Functional redundancy of the two co-expressed K+ channels may explain the lack of strong phenotypes in the single mutants. To investigate this possibility Kv3.1/3.3-double mutants were generated. Although Kv3.1/3.3-deficient mice are hyperactive, they display severe ataxia, intermittent tremor-like movements, myoclonus and hypersensitivity to ethanol. To understand the cellular origin and molecular basis of the different phenotypic traits, we propose to 1) examine mutant brains for possible structural and physiological alterations in areas where the two K+ channels are normally co-expressed using comparative immunohistochemistry and brain slice electrophysiology; 2) use the cDNA-microarray technology to detect possible alterations in expression levels of genes influencing neurotransmitter systems and other signaling molecules; and 3) attempt targeted rescue of distinct phenotypic traits (myoclonus, tremor, etc.) by crossing the double mutant to transgenic mice in which expression of Kv3.1 or Kv3.3 K+ channels is driven in distinct neuronal subpopulations by promoters with defined expression patterns. Knowledge generated by these studies will help define the physiological roles of Kv3.1 and Kv3.3 K+ channels and increase our understanding of the pathophysiology of some types of tremor, myoclonus and ethanol sensitivity, offering the possibility of future development of screening procedures, diagnostic tools and intervention strategies for individuals at risk.