Slo2/K Channels in Protect against Spontaneous and Induced Seizure-like Behavior Associated with an Increased Persistent Na Current.

Na sensitivity is a unique feature of Na-activated K (K) channels, making them naturally suited to counter a sudden influx in Na ions. As such, it has long been suggested that K channels may serve a protective function against excessive excitation associated with neuronal injury and disease. This hypothesis, however, has remained largely untested. Here, we examine K channels encoded by the () gene in males and females. We show that dSlo2/K channels are selectively expressed in cholinergic neurons in the adult brain, as well as in glutamatergic motor neurons, where dampening excitation may function to inhibit global hyperactivity and seizure-like behavior. Indeed, we show that effects of feeding a cholinergic agonist are exacerbated by the loss of dSlo2/K channels. Similar to mammalian Slo2/K channels, we show that dSlo2/K channels encode a TTX-sensitive K conductance, indicating that dSlo2/K channels can be activated by Na carried by voltage-dependent Na channels. We then tested the role of dSlo2/K channels in established genetic seizure models in which the voltage-dependent persistent Na current (I) is elevated. We show that the absence of dSlo2/K channels increased susceptibility to mechanically induced seizure-like behavior. Similar results were observed in WT flies treated with veratridine, an enhancer of I Finally, we show that loss of dSlo2/K channels in both genetic and pharmacologically primed seizure models resulted in the appearance of spontaneous seizures. Together, our results support a model in which dSlo2/K channels, activated by neuronal overexcitation, contribute to a protective threshold to suppress the induction of seizure-like activity. Slo2/K channels are unique in that they constitute a repolarizing K pore that is activated by the depolarizing Na ion, making them naturally suited to function as a protective "brake" against overexcitation and Na overload. Here, we test this hypothesis by examining how a null mutation of the ()/ gene affects seizure-like behavior in genetic and pharmacological models of epilepsy. We show that indeed the loss of dSlo2/K channels results in increased incidence and severity of induced seizure behavior, as well as the appearance of spontaneous seizure activity. Our results advance our understanding of neuronal excitability and protective mechanisms that preserve normal physiology and the suppression of seizure susceptibility.