Sex Differences and Estradiol Effects in MAPK and Akt Cell Signaling across Subregions of the Hippocampus

Abstract

<b><i>Introduction:</i></b> Rapid effects of estrogens within the hippocampus of rodents are dependent upon cell-signaling cascades, and activation of these cascades by estrogens varies by sex. Whether these pathways are rapidly activated within the dentate gyrus (DG) and CA1 by estrogens across sex and the anatomical longitudinal axis has been overlooked. <b><i>Methods:</i></b> Gonadally intact female and male rats were given either vehicle or physiological systemic low (1.1 µg/kg) or high (37.3 µg/kg) doses of 17β-estradiol 30 min prior to tissue collection. To control for the effects of circulating estrogens, an additional group of female rats was ovariectomized (OVX) and administered 17β-estradiol. Brains were extracted, and tissue punches of the CA1 and DG were taken along the longitudinal hippocampal axis (dorsal and ventral) and analyzed for key mitogen-activated protein kinase (MAPK) and protein kinase B (Akt) cascade phosphoproteins. <b><i>Results:</i></b> Intact females had higher Akt pathway phosphoproteins (pAkt, pGSK-3β, and pp70S6K) than males in the DG (dorsal and ventral) and lower pERK1/2 in the dorsal DG. Most effects of 17β-estradiol on cell signaling occurred in OVX animals. In OVX animals, 17β-estradiol increased cell signaling of MAPK and Akt phosphoproteins (pERK1/2, pJNK, pAkt, and pGSK-3β) in the CA1 and pERK1/2 and pJNK DG. <b><i>Discussion/Conclusions:</i></b> Systemic 17β-estradiol treatment rapidly alters phosphoprotein levels in the hippocampus, dependent on reproductive status, and intact females have greater expression of Akt phosphoproteins than that in intact males in the DG. These findings shed light on underlying mechanisms of sex differences in hippocampal function and response to interventions that affect MAPK or Akt signaling.

Social memory in female mice is rapidly modulated by 17β-estradiol through ERK and Akt modulation of synapse formation

“…Here, we have elucidated key intracellular mechanisms underlying the rapid facilitation of short-term social memory by E2. ERK and PI3K were previously found to be rapidly activated by estrogens(16,41,42) and necessary for long-term memory enhancements by E2(32,41–43,45). Our results suggest that these pathways are also necessary for the rapid enhancement of short-term social memory, thus underlying the adaptive dynamic modulation of social interactions by estrogens at times of changing social milieu.…”

“…Estrogens have long been known to elicit their effects by binding to intracellular estrogen receptors (ERs) that then dimerize, translocate to the nucleus, and directly affect gene transcription and protein expression (14). In addition to these delayed "classical" effects, estrogens affect molecular (15,16), cellular (17)(18)(19), systems (20,21), and behavioural (22)(23)(24)(25)(26) processes very rapidly (minutes) through intracellular mechanisms including activation of cell signaling cascades, such as the extracellular signal-regulated kinase (ERK) and phosphoinositide 3-kinase (PI3K) cascades.…”

“…Following activation (for instance, through memory task performance), these spines mature into persisting synapses (35). These estrogen-driven neurophysiological changes depend upon activity of cell signaling cascades, including ERK (16,17,34) and PI3K (17) pathways, which are also required for enhancement of object and spatial long-term memory consolidation by estrogens in female mice (32,(41)(42)(43)(44)(45). While ERK is known to be necessary for the rapid increase in CA1 dendritic spine density following E2 (32), the contributions of this kinase and the PI3K pathway to synapse formation in vivo are unknown.…”

KRSA: An R package and R Shiny web application for an end-to-end upstream kinase analysis of kinome array data

“…Recent research has identified sex-specific differences in AKT isoforms as a key factor in regulating neurobiological processes [ 36 ]. AKT was also differentially phosphorylated in hippocampal samples in the same direction as KRSA predictions [ 37 ]. Finally, another study identified differential expression of AKT-associated genes, but did not find significance in phosphorylation of AKT itself between males and females [ 38 ].…”

Exploration of beta-arrestin isoform signaling pathways in delta opioid receptor agonist-induced convulsions

“…Prior studies have indicated sex differences for δOR signaling in hippocampal areas (Harte-Hargrove et al, 2015;Mazid et al, 2016). Previous studies have also shown that female mice are more likely to show enhanced AKT phosphorylation, specifically in the hippocampus, in response to estrogen (Sheppard et al, 2021). If this is the case, then it is possible that inhibiting AKT with honokiol in male β-arrestin 1 knockout mice may have less of an effect on SNC80-induced seizures.…”