UC Irvine

Voltage-gated ion channels encoded by the members of KCNQ gene family (KCNQ2-5) conduct the M-type potassium current. Several neurotransmitters and signaling events have been shown to regulate the activity of the M-channel, including Ca2+ and muscarinic receptor-mediated suppression. We found that a change in the configuration of the KCNQ2 channel complex triggered by elevated intracellular Ca2+ lowers channel sensitivity to an essential co-factor, phosphatidylinositol 4,5-bisphosphate, which shuts down the channel. We also identified that a classical mechanism of M-current regulation mediated by muscarinic receptor activation requires KCNQ2 phosphorylation by PKC and dissociation of calmodulin, an auxiliary subunit of KCNQ2 channel complex. Based on these findings, we generated a knock-in mouse line that carries an alanine mutation at the key phosphorylation site of KCNQ2, KCNQ2(S559A). These mice show attenuated response to muscarinic-mediated M-current suppression, which enables us to address the role of physiological M-current suppression in vivo. Functionally, the M-current is one of the key modulators of synaptic plasticity with a proposed role in learning and memory. Thus, we aimed to identify the effects of M-current inhibition on memory processing. To discriminate between the memory processes mediated by different brain regions, we conducted perirhinal cortex-dependent and hippocampus-dependent memory tasks. KCNQ2(S559A) mice showed normal spatial memory as evidenced by successful performance with a 24 h retention interval. However, we observed a significant long-term recognition memory impairment in KCNQ2(S559A) mice with a 24 h retention interval. Inhibition of the M-current with XE991 during memory consolidation phase rescued memory deficit in KCNQ2(S559A) mice. Our mutant mice also showed deficits in long-term social odor memory, while maintaining normal olfactory responses, further implicating the M-current in memory processes mediated by perirhinal cortex. Finally, our behavioral findings were mirrored by a lower level of neuronal activation in perirhinal cortex of KCNQ2(S559A) mice compared to the wild-type during memory consolidation, as measured by c-fos expression 2 h after novel object recognition training. Our findings provide evidence for the proposed importance of M-current suppression during memory processing and offer a novel perspective on its role in recognition memory consolidation.