The Role of Potassium (I) Channel Interacting Protein 3 in Learning Strategies and Hippocampus-Dependent Memory in Male and Female Mice
Description
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