SUMMARY Ca2+-activated SK channels and voltage-gated A-type Kv4 channels shape dendritic excitatory postsynaptic potentials (EPSPs) in hippocampal CA1 pyramidal neurons. Synaptically evoked Ca2+ influx through N-methyl-D-aspartate receptors (NMDARs) activates spine SK channels, reducing EPSPs and the associated spine head Ca2+ transient. However, results using glutamate uncaging implicated Ca2+ influx through SNX-482 (SNX) sensitive Cav2.3 (R-type) Ca2+ channels as the Ca2+ source for SK channel activation. The present findings show that using Schaffer collateral stimulation the effects of SNX and apamin are not mutually exclusive and SNX increases EPSPs independent of SK channel activity. Dialysis with 1,2-bis(o-aminophenoxy)ethane-N’N’N’-tetraacetic acid (BAPTA), application of 4-Aminopyridine (4-AP), expression of a Kv4.2 dominant negative subunit, and dialysis with a KChIPs antibody occluded the SNX-induced increase of EPSPs. The results suggest two distinct Ca2+ signaling pathways within dendritic spines, that links Ca2+ influx through NMDARs to SK channels and Ca2+ influx through R-type Ca2+ channels to Kv4.2-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.

In pyramidal neurons such as hippocampal area CA1 and basolateral amygdala, a slow afterhyperpolarization (sAHP) follows a burst of action potentials, which is a powerful regulator of neuronal excitability. The sAHP amplitude increases with aging and may underlie age related memory decline. The sAHP is due to a Ca2+-dependent, voltage-independent K+ conductance, the molecular identity of which has remained elusive until a recent report suggested the Ca2+-activated K+ channel, IK1 (KCNN4) as the sAHP channel in CA1 pyramidal neurons. The signature pharmacology of IK1, blockade by TRAM-34, was reported for the sAHP and underlying current. We have examined the sAHP and find no evidence that TRAM-34 affects either the current underling the sAHP or excitability of CA1 or basolateral amygdala pyramidal neurons. In addition, CA1 pyramidal neurons from IK1 null mice exhibit a characteristic sAHP current. Our results indicate that IK1 channels do not mediate the sAHP in pyramidal neurons.DOI: http://dx.doi.org/10.7554/eLife.11206.001