Sex- and estrous-cycle dependent dorsal hippocampal phosphoproteomic changes induced by low-dose ketamine

Abstract

Numerous emotional and cognitive processes mediated by the hippocampus present differences between sexes and can be markedly influenced by hormonal status in males and females of several species. In rodents, the dorsal hippocampus (dHPC) is known to contribute to the rapid antidepressant actions of the NMDA receptor antagonist ketamine. We and others have demonstrated a greater sensitivity to the fast-acting antidepressant ketamine in female versus male rats that is estrogen- and progesterone-dependent. However, the underlying mechanisms remain unclear. Using an acute low dose (2.5 mg/kg) of ketamine that is behaviorally effective in female but not male rats, a label-free phosphoproteomics approach was employed to identify ketamine-induced changes in signaling pathway activation and phosphoprotein abundance within the dHPC of intact adult male rats and female rats in either diestrus or proestrus. At baseline, males and females showed striking dissimilarities in the dHPC proteome and phosphoproteome related to synaptic signaling and mitochondrial function—differences also strongly influenced by cycle stage in female rats. Notably, phosphoproteins enriched in PKA signaling emerged as being both significantly sex-dependent at baseline and also the primary target of ketamine-induced protein phosphorylation selectively in female rats, regardless of cycle stage. Reduced phosphoprotein abundance within this pathway was observed in males, suggesting bi-directional effects of low-dose ketamine between sexes. These findings present biological sex and hormonal milieu as critical modulators of ketamine’s rapid actions within this brain region and provide greater insight into potential translational and post-translational processes underlying sex- and hormone-dependent modulation of ketamine’s therapeutic effects.

Sex- and age-dependent effects of chronic corticosterone exposure on depressive-like, anxiety-like, and fear-related behavior: Role of amygdala glutamate receptors in the rat

“…For example, while one study showed that the basal and lateral parts of the amygdala show greater inhibition during low estradiol phases (diestrus) and high estradiol phases (proestrus), respectively (Blume et al, 2017), another indicated that GluR1 and GluR2/3 expression is not changed by gonadal hormone manipulations in either sex, though other sexually dimorphic brain regions like the hypothalamus did show upregulation of these receptors following hormone replacement with either testosterone in males, or estradiol in females (Diano et al, 1997). Interestingly, the enhanced effects of ketamine in females appear to be mediated by ovarian hormones (Dossat et al, 2018;Saland et al, 2022), and estrogen plus ketamine or its metabolites ((2R,6R)-HNK and (2S,6S)-HNK) had additive effects on increasing Gria1-4 expression, suggesting that estradiol interacts with AMPA receptors to enhance the effects of ketamine (Ho et al, 2018). This finding may shed light on a potential mechanism of the therapeutic potential of ketamine in treating depression in females, though further studies in neurons is warranted.…”

Sex and Estrous Cycle Are Not Mediators of S-Ketamine’s Rapid-Antidepressant Behavioral Effects in a Genetic Rat Model of Depression

“…Although there are few studies to rely on, it seems the difference in response to ketamine between men and women as well as women premenopause and postmenopause is slight ( Coyle and Laws, 2015 ; Freeman et al, 2019 ). However, preclinical studies fail to replicate all the findings of clinical studies and have reported sex-specific and estrous cycle–specific differences in ketamine’s antidepressant effect, relying on behavioral despair to measure depressive-like behaviors ( Carrier and Kabbaj, 2013 ; Franceschelli et al, 2015 ; Sarkar and Kabbaj, 2016 ; Dossat et al, 2018 ; Ponton et al, 2022 ; Saland et al, 2022 ). Nevertheless, most preclinical studies have not used animal models of depression ( Ponton et al, 2022 ), which could be a potential deviation from real life and a source of discrepancies.…”