Small-conductance Ca2+-activated K+ channels: Heterogeneous affinity in rat brain structures and cognitive modulation by specific blockers

Small-conductance calcium-activated potassium channels (KCa2) generating the medium afterhyperpolarization seen after an action potential modulate the neuronal integration signal. The effects of two KCa2 channel blockers, apamin, specific to KCa2.2 and KCa2.3 channels, and lei-Dab7, which binds to KCa2.2 channels only, were compared to evaluate the involvement of KCa2 channel subunits in behavior, spatial learning and memory in rats. Intracerebroventricular (9-5 ng) injections of lei-dab7 decreased locomotor activity, food intake and body weight in rats deprived of food. A dose of 3 ng lei-Dab7 had no effect on these types of behavior. We therefore used this dose for attention and memory tasks. No modification to attention or memory was observed in a spatial radial-arm maze task with rats given 3 ng lei-Dab7, whereas apamin (0.3 ng) improved reference memory and accelerated changes of strategy from egocentric to allocentric. These findings suggest that KCa2.3 blockade improves memory in rats. Lei-Dab7 entirely outcompeted the binding of iodinated apamin to 64 brain structures (mean IC50: 34.5 nM), although IC50 values were highly variable. By contrast, overall IC50 values for apamin were close to mean values (11.3 pM). The very low affinity of the hippocampus and neocortex for lei-Dab7 may account for the absence of a behavioral effect of this compound. The variability of IC50 values suggests that KCa2 channel composition varies considerably as a function of the brain structure considered.