Kv3.3 channels at the Purkinje cell soma are necessary for generation of the classical complex spike waveform.
Voltage-gated potassium channel subunit Kv3.3 is prominently expressed in cerebellar Purkinje cells and is known to be important for cerebellar function, as human and mouse movement disorders result from mutations in Kv3.3. To understand these behavioral deficits, it is necessary to know the role of Kv3.3 channels on the physiological responses of Purkinje cells. We studied the function of Kv3.3 channels in regulating the synaptically evoked Purkinje cell complex spike, the massive postsynaptic response to the activation of climbing fiber afferents, believed to be fundamental to cerebellar physiology. Acute slice recordings revealed that Kv3.3 channels are required for generation of the repetitive spikelets of the complex spike. We found that spikelet expression is regulated by somatic, and not by dendritic, Kv3 activity, which is consistent with dual somatic-dendritic recordings that demonstrate spikelet generation at axosomatic membranes. Simulations of Purkinje cell Na+ currents show that the unique electrical properties of Kv3 and resurgent Na+ channels are coordinated to limit accumulation of Na+ channel inactivation and enable rapid, repetitive firing. We additionally show that Kv3.3 knock-out mice produce altered complex spikes in vitro and in vivo, which is likely a cellular substrate of the cerebellar phenotypes observed in these mice. This characterization presents new tools to study complex spike function, cerebellar signaling, and Kv3.3-dependent human and mouse phenotypes.
Zagha
Edward
E
Department of Physiology and Neuroscience, New York University School of Medicine, New York, New York 10016, USA.
Lang
Eric J
EJ
Rudy
Bernardo
B
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D000831:Animals, Newborn; D002462:Cell Membrane / Q000187:drug effects / Q000502:physiology*; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D066298:In Vitro Techniques; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D026902:Potassium Channel Blockers / Q000494:pharmacology; D011689:Purkinje Cells / Q000187:drug effects / Q000502:physiology*; D051670:Shaw Potassium Channels / Q000037:antagonists & inhibitors / Q000502:physiology*
C085724:Kcnc3 protein, mouse; D026902:Potassium Channel Blockers; D051670:Shaw Potassium Channels