TRESK channel contributes to depolarization-induced shunting inhibition and modulates epileptic seizures.

Glutamatergic and GABAergic synaptic transmission controls excitation and inhibition of postsynaptic neurons, whereas activity of ion channels modulates neuronal intrinsic excitability. However, it is unclear how excessive neuronal excitation affects intrinsic inhibition to regain homeostatic stability under physiological or pathophysiological conditions. Here, we report that a seizure-like sustained depolarization can induce short-term inhibition of hippocampal CA3 neurons via a mechanism of membrane shunting. This depolarization-induced shunting inhibition (DShI) mediates a non-synaptic, but neuronal intrinsic, short-term plasticity that is able to suppress action potential generation and postsynaptic responses by activated ionotropic receptors. We demonstrate that the TRESK channel significantly contributes to DShI. Disruption of DShI by genetic knockout of TRESK exacerbates the sensitivity and severity of epileptic seizures of mice, whereas overexpression of TRESK attenuates seizures. In summary, these results uncover a type of homeostatic intrinsic plasticity and its underlying mechanism. TRESK might represent a therapeutic target for antiepileptic drugs. [Display omitted] • A sustained seizure-like depolarization induces a transient shunting inhibition • This non-synaptic form of short-term plasticity contributes to seizure termination • TRESK, a subtype of K⁺ channels, contributes to this shunting inhibition • Activating TRESK shortens seizure duration and prolongs postictal depression Huang et al. find sustained depolarization-induced shunting inhibition (DShI) which is induced by seizure-like and seizure-mimicking sustained depolarizations. The inhibitory action and time course of DShI is sufficient to explain the termination of ictal epileptiform activity and postictal depression. TRESK contributes to DShI and modulates seizures. [ABSTRACT FROM AUTHOR]