Small conductance Ca(2+)-activated K(+) channels (SK, K(Ca2.1), K(Ca2.2), K(Ca2.3)) are expressed at high levels in brain regions critical for learning and memory. The activation of dendritic SK channels limits the induction of synaptic plasticity that may underlie hippocampal and amygdala dependent memory. EBIO facilitates SK channel activation by increasing their sensitivity to calcium. The compound CyPPA selectively activates SK2 and SK3 channels in a similar manner. To date there has been no report of the effects of SK channel activators on memory. Therefore, the present study examined the effects of systemic EBIO on mice in a behavioral task battery. Significant effects of EBIO on memory and motor activity were validated and extended by examining the effects of systemic CyPPA. Systemic EBIO and CyPPA both produced a transient decline in locomotor behavior. Neither SK channel activator affected anxiety. EBIO (17.5 mg/kg) impaired the encoding, but not retrieval, of object memory in a spontaneous object recognition task. A similar impairment of object memory encoding was observed in CyPPA (15 mg/kg)-treated mice. These memory-impairing effects were not due to changes in motivation, attention or movement. Systemic EBIO did not affect contextual or cued fear memory after conditioning with a 3 tone (CS)-footshock (US) pairing protocol or a 1 CS-US pairing protocol. Interestingly, apamin (0.4 mg/kg) enhanced contextual fear memory in mice conditioned with a 1 CS-US pairing protocol. These results suggest that SK channel activation impairs the encoding of non-aversive memory but not memory for aversive events. These data support converging evidence that SK channels regulate cellular mechanisms of memory encoding.