Blockade of IP3-mediated SK channel signaling in the rat medial prefrontal cortex improves spatial working memory.

Planning and directing thought and behavior require the working memory (WM) functions of prefrontal cortex. WM is compromised by stress, which activates phosphatidylinositol (PI)-mediated IP3-PKC intracellular signaling. PKC overactivation impairs WM operations and in vitro studies indicate that IP3 receptor (IP3R)-evoked calcium release results in SK channel-dependent hyperpolarization of prefrontal neurons. However, the effects of IP3R signaling on prefrontal function have not been investigated. The present findings demonstrate that blockade of IP3R or SK channels in the prefrontal cortex enhances WM performance in rats, suggesting that both arms of the PI cascade influence prefrontal cognitive function.