Nk3R Blockade Has Sex-divergent Effects on Memory in Mice

Background: Memory consolidation is a process required for the formation of long-term memories. The G-protein-coupled receptor (GPCR) neurokinin-3-receptor (Nk3R) and its interactions with sex hormones seem important for the modulation of fear memory consolidation: Nk3R antagonism in male mice impairs fear memory, but enhances it in females. However, the involvement of the Nk3R as a modulator of other memories in both sexes remains unexplored.

Methods: We use the novel object recognition paradigm to test the effect of a systemic blockade of Nk3R during memory consolidation. Further, we assess the expression of estrogen receptor α, estrogen receptor β, and androgen receptor and heterodimerization with Nk3R in the medial prefrontal cortex (mPFC) and dorsal hippocampus (DH) of mice.

Results: Nk3R systemic antagonism elicited decreased memory consolidation in males while it enhanced it in females during proestrus. Nk3R analysis in the different subregions of the mPFC and the DH showed a higher expression in males than females. Moreover, females presented upregulation of the androgen receptor in the CA1 and the estrogen receptor beta in the cingulate cortex, CA1, and dentate gyrus. Overall, males presented an upregulation of the estrogen receptor alpha. We also explored the heterodimerization of GCPR membrane sex hormone receptors with the Nk3R. We found a higher percentage of Nk3R-membrane G-protein estrogen receptors heterodimers in the prelimbic cortex of the mPFC in females, suggesting an interaction of estradiol with Nk3R in memory consolidation. However, males presented a higher percentage of Nk3R-membrane G-protein androgen receptors heterodimers compared to females, pointing to an interaction of testosterone with Nk3R in memory consolidation.

Conclusion: These data propose novel ideas on functional interactions between Nk3R, sex hormones, estrogen receptors, and androgen receptors in memory consolidation.