Abstracts

Rationale: Erg-like (Elk, Kv12) voltage-gated K+ channels are expressed throughout the nervous system but their role in neuronal physiology has yet to be described. The characteristic biophysical feature of these channels is a hyperpolarized activation range which suggests a role in determining the sub-threshold excitability of neurons. We sought to determine how Kv12 channels contribute to neuronal signaling. Methods: We produced a mouse knockout of Kv12.2 (Elk2), a channel that is abundantly expressed in forebrain excitatory neurons. We performed cortical EEG recordings, behavioural tests and electrophysiological analyses on cultured neurones. Results: EEG recordings from Kv12.2 -/- mice revealed continuous interictal spike-wave activity accompanied by sporadic spontaneous non-convulsive seizures. Both the knockout and heterozygotes show hypersensitivity to the chemoconvulsant pentylenetetrazole (PTZ). Locomotor activity, coordination and stress responses are not affected in open field and rotarod tests. The mouse phenotype is recapitulated at the cellular level, as cultured hippocampal neurons from KO mice have depolarized resting potentials, increased input resistance and low action potential thresholds. As a result, spontaneous firing is greatly increased relative to WT and maximal firing rates can be elicited with significantly less current injection. Conclusions: We propose that Kv12.2 provides an important and previously unrecognized resting conductance that protects against synchronous discharge in seizure-susceptible circuits.