DREAM/calsenilin/KChIP3 modulates strategy selection and estradiol-dependent learning and memory

Abstract

Downstream regulatory element antagonist modulator (DREAM)/calsenilin(C)/K+ channel interacting protein 3 (KChIP3) is a multifunctional Ca 2+ -binding protein highly expressed in the hippocampus that inhibits hippocampus-sensitive memory and synaptic plasticity in male mice. Initial studies in our lab suggested opposing effects of DR/C/K3 expression in female mice. Fluctuating hormones that occur during the estrous cycle may affect these results. In this study, we hypothesized that DR/C/K3 interacts with 17b-estradiol, the primary estrogen produced by the ovaries, to play a role in hippocampus function. We investigated the role of estradiol and DR/C/K3 in learning strategy in ovariectomized (OVX) female mice. OVX WT and DR/C/K3 knockout (KO) mice were given three injections of vehicle (sesame oil) or 17b-estradiol benzoate (0.25 mg in 100 mL sesame oil) 48, 24, and 2 h before training and testing. DR/C/K3 and estradiol had a time-dependent effect on strategy use in the female mice. Male KO mice exhibited enhanced place strategy relative to WT 24 h after pre-exposure. Fear memory formation was significantly reduced in intact female KO mice relative to intact WT mice, and OVX reduced fear memory formation in the WT, but had no effect in the KO mice. Long-term potentiation in hippocampus slices from female mice was enhanced by circulating ovarian hormones in both WT and DR/C/K3 KO mice. Paired-pulse depression was not affected by ovarian hormones but was reduced in DR/C/K3 KO mice. These results provide the first evidence that DR/C/K3 plays a timing-dependent role in estradiol regulation of learning, memory, and plasticity.

Global Gene Knockout of Kcnip3 Enhances Pain Sensitivity and Exacerbates Negative Emotions in Rats

“…In fact, previous studies in Kcnip3 -/- mice demonstrated that they have slightly increased anxiety levels compared to the wild-type controls, and no significant difference was observed compared to the wild-type control (Alexander et al, 2009). Another study in female Kcnip3 -/- mice also showed that the Kcnip3 gene deletion did not affect the anxiety level in the ovariectomized mice receiving or not receiving estradiol injections (Tunur et al, 2013). However, both our studies from elevated plus maze and open field tests indicated that Kcnip3 -/- rats had a higher anxiety level compared to the wild-type rats post CFA injection.…”

Emerging Role of DREAM in Healthy Brain and Neurological Diseases

“…DREAM is mainly expressed at the presynaptic level in neurons [36], where it participates in the regulation of glutamate release in the synaptic cleft [37] and plays a role in hippocampus-sensitive memory and synaptic plasticity [38][39][40]. In addition, DREAM binds to the NR1 subunit of the main receptor involved in synaptic plasticity, NMDAR, causing a reduced surface expression of this ligand-gated ion channel and, ultimately, a decrease in NMDAR-mediated currents [31].…”

Flavonoids as a Natural Enhancer of Neuroplasticity—An Overview of the Mechanism of Neurorestorative Action

“…In addition, resveratrol reduced the expressions of Aβ and ERβ, as well as increasing the expressions of choline acetyltransferase (ChAT), estradiol, and both the protein and mRNA of Erα [ 104 ]. Significantly, it is suggested that female sex hormones positively correlate with the improvement of cognitive functions and memory, and the increased secretion of neurotransmitters indirectly affects synaptogenesis [ 105 , 106 , 107 ]. Another study in vitro showed that the inhibition of Aβ aggregation by resveratrol (100 µM) was achieved by regulating the following proteins involved in proteostasis: ubiquitin-like protein (UBL) and X-box 1 binding protein (XBP-1) [ 108 ].…”