Selective Activation of the SK1 Subtype of Small Conductance Ca2+-Activated K+Channels by 4-(2-Methoxyphenylcarbamoyloxymethyl)-piperidine-l-carboxylic Acid tert-Butyl Ester(GW542573X) in C57BL/6J Mice lmpairs Hippocampal-Dependent Memory.

Small conductance Ca2+ -activated K+ (SK) channels have physiological roles in
learning and memory, intrinsic excitability, synaptic transmission and plasticity, and addiction.
While SK2 and SK3 channels have been studied, the role of SK1 has not yet been determined
due to the prior lack of gene-specific antibodies and agonists. SK1 are robustly expressed in the
CA1 pyramidal neurons of the hippocampus and modulate their excitability by affecting
afterhyperpolarization. SK1 subunits are only sited in the plasma membrane when co-expressed
with SK2 or SK3. Co-expressed and co-assembled SK1, SK2, and SK3 subunits form functional
apamin-sensitive channels. SK1 are not apamin selective, suggesting the overriding hypothesis
that SK1 is a subunit of heteromeric SK channels that bind specific interacting proteins. We
examined the effect of a new SK1 selective activator, GW542573X, on hippocampal dependent
object memory in male C57BL/6J mice. The results showed that activating SK1 channels by
systemic injection of the SK1 agonist GW542573X before the sample session, led to impaired
object memory in mice 24 h later. Mice treated with GW542573X acquired the sample object
exploration criterion in a similar latency as the vehicle-treated mice.GW542573X treated mice
exhibited significantly less preference for exploring the novel object during the test session
compared to the vehicle-treated mice. These results suggest that the SK1 activator disrupted the
encoding of object memory without affecting the motivation to explore objects. This supports a
role for SK1 in the modulation of hippocampal synaptic plasticity and hippocampal-dependent
memory.