Accumulating evidence indicates that estrogens modulate cognitive performance, particularly via shifts in learning strategies. Ovariectomy in female rats to eliminate circulating ovarian hormones biases rats toward striatum-dependent response strategy use and reduces the hippocampus-dependent place strategy use compared to intact or estradiol-treated animals. However, the molecular mechanism by which these hormones act within the hippocampus is still unclear K+ Channel Interacting Protein (K3/DR/C) is a protein that interacts with Kv4 potassium channels at the membrane and can also act as a transcription factor in the nucleus. In previous studies, we found that male K3/DR/C KO mice exhibited enhanced contextual fear memory, but female K3/DR/C KO did not. In this study, we further tested hippocampus-dependent spatial memory in female and male K3/DR/C KO and WT mice. Mice were tested on a water plus-maze task that could be solved by either a place or response strategy. Interestingly, female K3/DR/C KO mice showed contrasting effects on short- and long-term benefits of pre-exposure with increased preference for place strategy immediately after pre-exposure and preference for response strategy 24 hours later. On the other hand, male K3/DR/C KO mice favored place strategy use 24 hours after the pre-exposure, compared to same day pre-exposure group and WTs In addition, we investigated the effect of ovarian hormones on synaptic plasticity in these mice and found that the perforant path-dentate granule cell synapse in hippocampus slices from K3/DR/C KO mice exhibited enhanced long-term potentiation (LTP) relative to slices from WT animals, and this enhanced plasticity was dependent on the presence of ovarian hormones. Additionally, we investigated K3/DR/C's possible role in estrogen receptor alpha-dependent transcription in transfected neuroblastoma cells We also investigated K3/DR/C's role in a more dentate gyrus-sensitive pattern separation task, and showed that K3/DR/C KO male mice exhibit enhanced performance in this task. Western blot and electrophysiology studies we conducted suggested K3/DR/C KO dentate gyrus may have more mature neurons, resulting in more efficient dentate gyrus. Together these data suggest that K3/DR/C modulates spatial memory and plasticity enhancement by estradiol. K3/DR/C also regulates pattern separation in male mice by altering the efficiency of dentate gyrus
