Title : Increasing SK 2 Channel Activity Impairs

29 Enhanced intrinsic neuronal excitability of hippocampal pyramidal neurons via 30 reductions in the postburst afterhyperpolarization (AHP) has been hypothesized to be a 31 biomarker of successful learning. This is supported by considerable evidence that 32 pharmacological enhancement of neuronal excitability facilitates learning. However, it 33 has yet to be demonstrated that pharmacological reduction of neuronal excitability 34 restricted to the hippocampus can retard acquisition of a hippocampus-dependent task. 35 Hence, the present study was designed to address this latter point using a small 36 conductance potassium (SK) channel activator NS309 focally applied to the dorsal 37 hippocampus. SK channels are important contributors to intrinsic excitability, as 38 measured by the medium postburst AHP. NS309 increased the medium AHP and 39 reduced EPSP width of CA1 neurons in vitro. In vivo, NS309 reduced the spontaneous 40 firing rate of CA1 pyramidal neurons and impaired trace eyeblink conditioning in rats. 41 Conversely, trace eyeblink conditioning reduced levels of SK2 channel mRNA and 42 protein in the hippocampus. Therefore, the present findings indicate that modulation of 43 SK channels is an important cellular mechanism for associative learning and further 44 support postburst AHP reductions in hippocampal pyramidal neurons as a biomarker of 45 successful learning. 46 47