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

Abstract

Social memory is essential to the functioning of a social animal within a group. Estrogens can affect social memory too quickly for classical genomic mechanisms. Previously, 17β-estradiol (E2) rapidly facilitated short-term social memory and increased nascent synapse formation, these synapses being potentiated following neuronal activity. However, what mechanisms underlie and coordinate the rapid facilitation of social memory and synaptogenesis are unclear. Here, the necessity of extracellular signal-regulated kinase (ERK) and phosphoinositide 3-kinase (PI3K) signaling for rapid facilitation of short-term social memory and synaptogenesis was tested. Mice performed a short-term social memory task or were used as task-naïve controls. ERK and PI3K pathway inhibitors were infused intradorsal hippocampally 5 min before E2 infusion. Forty minutes following intrahippocampal E2 or vehicle administration, tissues were collected for quantification of glutamatergic synapse number in the CA1. Dorsal hippocampal E2 rapid facilitation of short-term social memory depended upon ERK and PI3K pathways. E2 increased glutamatergic synapse number (bassoon puncta positive for GluA1) in task-performing mice but decreased synapse number in task-naïve mice. Critically, ERK signaling was required for synapse formation/elimination in task-performing and task-naïve mice, whereas PI3K inhibition blocked synapse formation only in task-performing mice. While ERK and PI3K are both required for E2 facilitation of short-term social memory and synapse formation, only ERK is required for synapse elimination. This demonstrates previously unknown, bidirectional, rapid actions of E2 on brain and behavior and underscores the importance of estrogen signaling in the brain to social behavior.

Rapid nongenomic estrogen signaling controls alcohol drinking behavior

“…Here, we find that rapid E2 signaling at membrane-associated receptors promotes synaptic excitation of BNST CRF neurons that are required for motivated alcohol drinking and more engaged when females are in a high ovarian E2 state. Similar to our finding that E2 increases glutamatergic synaptic transmission at BNST CRF synapses, it has been shown to enhance excitatory neurotransmission and excitation in the hippocampus and hypothalamus via mechanisms such as increasing glutamate release, dendritic spine formation, and long term potentiation 21,75,91,92 .The current reports on the role of rapid E2 in behavioral control show that social memory is dependent on rapid-E2 mediated ERK and PI3K actions in the hippocampus 22 , and E2-mediated enhancement of cocaine self-administration requires mGluR5 activity in ovariectomized females 93 , indicating the importance of excitatory synaptic transmission in E2’s behavioral role. Future work is necessary to fully elucidate the signaling mechanism underlying the role of rapid E2 in driving BNST CRF neuron activity to drive motivated alcohol drinking.…”

“…However, it can also act at membraneassociated ERs in the brain to rapidly modulate synaptic transmission and intrinsic excitability in brain regions including the hippocampus, hypothalamus, striatum, nucleus accumbens, and amygdala 5,[11][12][13][14][15][16][17] . Pioneering work has established that rapid E2 signaling plays a critical role in the mediation of behavior, as acute administration of E2 or ER modulators can modulate behaviors including aggression 18,19 and reproductive/sexual behavior 20 in gonadectomized male rodents, as well as learning and memory 21,22 and psychostimulant self-administration and hyperlocomotion in ovariectomized female rodents [23][24][25] , within an hour of administration. However, the role of rapid E2 signaling in intact rodents is relatively unknown, with the exception of a report showing that acute pharmacological inhibition of E2 synthesis rapidly inhibits male sexual behavior 26 .…”

Estradiol regulates local synthesis of synaptic proteome via sex-specific mechanisms

“…We focused on the impact of estradiol-induced increased expression of GluN2B and PSD-95, as both proteins have been implicated in mediating the effects of this steroid on synaptic plasticity and behaviour (Akama & McEwen, 2003; Smith & McMahon, 2006; Liu et al ., 2008; Avila et al ., 2017). Estradiol has been reported to increase the expression of PSD-95 located at synapses (Akama & McEwen, 2003; Liu et al ., 2008; Srivastava et al ., 2010; Sellers et al ., 2015b), and are thought to contribute to the increased targeting of AMPA receptors to synapses, and thus drive estradiol- facilitation of synaptic plasticity (Srivastava et al ., 2008; Phan et al ., 2015; Sheppard et al ., 2023). Multiple studies have also reported that GluN2B-containing NMDARs are critical for estradiol-induced enhancement in LTP (Smith & McMahon, 2006; Snyder et al ., 2011; Vedder et al ., 2013; Smith et al ., 2016).…”

“…These effects occur in parallel to estradiol- induced dendritic spine formation (Phan et al ., 2015; Tuscher et al ., 2016; Luine et al ., 2018), and increased expression of excitatory synaptic proteins. For example, estradiol increases the synaptic expression of GluN2B-containing N -methyl-D- aspartate receptors (NMDARs), PSD-95 and GluA1-containing α-amino-3-hydroxy-5- methyl-4-isoxazoleproprionic acid receptors (AMPARs) (Jelks et al ., 2007; Liu et al ., 2008; Smith et al ., 2009; Smith et al ., 2016; Avila et al ., 2017; Sheppard et al ., 2023). These changes in dendritic spine density and synaptic proteome are thought to underlie estradiol’s ability to modulate synaptic transmission and plasticity, and thus, its effects on cognition (Srivastava et al ., 2013; Vedder et al ., 2013; Luine et al ., 2018; Sheppard et al ., 2019).…”

“…Estradiol- mediated membrane-initiated signalling is characterised by activation of signalling kinase pathways, such as the extracellular signal-regulated kinase (ERK) and mammalian target of Rapamycin (mTOR) pathways, as well as the rearrangement of the actin cytoskeleton, and moreover, is thought to be independent of gene transcription (Sellers et al ., 2015a; Taxier et al ., 2020). Consistent with this, activation of kinases pathways, as well as effects on dendritic spines, synaptic proteome and function have typically been described to occur within minutes of estradiol treatment (Woolley, 2007; Phan et al ., 2015; Sellers et al ., 2015a; Luine et al ., 2018; Taxier et al ., 2020; Sheppard et al ., 2023). However, the effects of estradiol on the synaptic proteome, dendritic spines and synaptic function have also been described to last for hours or days (Woolley & McEwen, 1994; Smith & McMahon, 2006; Liu et al ., 2008; Tuscher et al ., 2016).…”