The SK2-Long Isoform Directs Synaptic Localization and Function of SK2-containing channels

SK2-containing channels are expressed in the postsynaptic density (PSD) of dendritic spines on mouse CA1 pyramidal neurons, and influence synaptic responses, plasticity, and learning. The SK2 gene encodes two isoforms differing only in the length of the N-terminal domain. SK2-Long (SK2-L) and SK2-Short (SK2-S) are co-expressed in CA1 pyramidal neurons and likely form heteromeric channels. In mice lacking SK2-L (SK2-Sonly mice), SK2-S-containing channels were expressed in the extrasynaptic membrane, but were excluded from the PSD. The SK channel contribution to EPSPs was absent in SK2-Sonly mice, and was restored by SK2-L re-expression. In slices from wild type mice, blocking SK channels increased the amount of long-term potentiation (LTP) induced in area CA1 but was without effect in SK2-Sonly mice. Further, SK2-Sonly mice outperformed wild type mice in the novel object recognition task. These results show that SK2-L directs synaptic SK2-containing channel expression, important for normal synaptic signaling, plasticity, and learning.