The Role of Kv3.3 Voltage-Gated Potassium Channel Expression in Cerebellar Purkinje Cells in Motor Coordination



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I examined the role of the Kv3.3 voltage-gated potassium channel (Kv) subunit encoded by the Kcnc3 gene in cerebellar Purkinje cells in determining the properties of complex spikes and in motor coordination. Kv3 channels (Kv3.1-Kv3.4) enable high-frequency firing by activating and deactivating rapidly during and after action potentials, respectively. Kv3.3 subunits are expressed in distinct neuronal cell-types in regions throughout the CNS including the cerebellum, an area important for motor control. Kcnc3-null mice exhibit a reduced frequency and broadening of spikes in Purkinje cells as well as ataxia, as in spinocerebellar ataxia type 13 (SCA13) patients who carry mutations in KCNC3. In contrast to Purkinje cells, in other neuronal cell types Kv3.3 is co-expressed with considerable levels of other Kv3 subunits that potentially complement the loss of Kv3.3, suggesting that Purkinje cellular Kv3.3 function may be important for motor coordination. I restored expression of the Kv3.3b splice variant specifically in Purkinje cells by crossing transgenic mice that express Kv3.3b under the control of the tetracycline transactivator with a line expressing the latter exclusively in Purkinje cells on a Kcnc3-null background. Whole-cell recordings in slices at the resting potential of complex spikes in Purkinje neurons revealed weakened bursts but lengthened simple spike pauses thereafter in Kcnc3-null mice. Restoration of Kv3.3 completely rescued all spike parameters and sufficed to rescue motor coordination measured by counting slips traversing a 1-cm beam and recording lateral deviation of gait on a force plate actometer. The Kcnc3-null mice heterozygous for Kcnc1 were partially rescued. Gait analysis indicated the ataxia arises from hypermetria not gait ataxia. When Kcnc1 alleles are additionally ablated gait ataxia appears. Spikes in large, glutamatergic deep cerebellar nuclear (DCN) neurons, which express all four Kv3 units, broaden concurrently, but remain largely normal in Kcnc3-null mice, suggesting functional redundancy here could underlie severe ataxia in Kcnc1/Kcnc3 double-null mutants. Therefore, Kv3.3 function in Purkinje neurons is sufficient to account for the hypermetric Kcnc3-null phenotype and impaired complex spiking represents a potential underlying mechanism in addition to broadened, decelerated simple spiking. The behavioral rescue, fast spiking in DCN neurons and normal gait require Kcnc1.