SK3-overexpression drives sex-dimorphic working and social memory impairment in mice

Abstract

Although sex differences in memory tasks dependent on hippocampal function have been described in several species, including rodents and humans, the exact mechanisms involved remain debatable. The function of the small-conductance Ca2+-activated K+ channel type 3 has been associated with cognitive deficits, and its overexpression in male mice (T/T) induces shrinkage of the hippocampus. Here we describe that opposite to the observation in males, in female mice, SK3-induced-reduction in the volume of the hippocampal formation does not interfere with working and social memory performance. Male, but not female T/T mice showed decreased adult hippocampal neurogenesis and down-regulation of the expression of the genes related to Akt/mTOR and MAP kinase pathways. T/T male mice exhibit impaired estrogen and Neurogulin 1 signaling. An increased number of filopodia spines is observed in the dentate gyrus (DG). Our results suggest a fine-tune modulation of SK3 expression participates in the sex-dependent function of the hippocampus via estrogen signaling and neuroplasticity in the DG. Our results reinforce the importance of testing male and female mice while conducting experiments with transgenic mice.