The goal of this proposal is to examine the role of small-conductance Ca2+-activated K+ (SK) channels in hippocampal-dependent memory. The hippocampus is essential for declarative memory, and understanding the molecular mechanisms of hippocampal-dependent memory will aid in developing treatments for declarative memory disorders. In the hippocampus, SK channels underlie the medium component of the after-hyperpolarizing current (ImAHP) that follows an action potential. Blocking SK channels with apamin abolishes the ImAHP and enhances neuronal excitability. Activation of SK channels in the hippocampus with EBIO increases the ImAHP and reduces cell excitability (Pedarzani et al. 2001). Apamin enhances the induction of NMDAR-dependent hippocampal synaptic plasticity and enhances spatial and non-spatial hippocampal-dependent memory encoding in mice (Stackman et al. 2002). These findings suggest a model where hippocampal SK channels inhibit hippocampal-dependent plasticity and memory encoding. This model will be tested with intra-hippocampal administration of apamin or EBIO prior to training in two hippocampal memory tasks. The specific role of SK2 channels in the ImAHP and memory encoding will be tested with transgenic mice that conditionally over-express SK2 channels.
