Memory-Related Synaptic Plasticity Is Sexually Dimorphic in Rodent Hippocampus

Abstract

Men are generally superior to women in remembering spatial relationships, whereas the reverse holds for semantic information, but the neurobiological bases for these differences are not understood. Here we describe striking sexual dimorphism in synaptic mechanisms of memory encoding in hippocampal field CA1, a region critical for spatial learning. Studies of acute hippocampal slices from adult rats and mice show that for excitatory Schaffer-commissural projections, the memory-related long-term potentiation (LTP) effect depends upon endogenous estrogen and membrane estrogen receptor α (ERα) in females but not in males; there was no evident involvement of nuclear ERα in females, or of ERβ or GPER1 (G-protein-coupled estrogen receptor 1) in either sex. Quantitative immunofluorescence showed that stimulation-induced activation of two LTP-related kinases (Src, ERK1/2), and of postsynaptic TrkB, required ERα in females only, and that postsynaptic ERα levels are higher in females than in males. Several downstream signaling events involved in LTP were comparable between the sexes. In contrast to endogenous estrogen effects, infused estradiol facilitated LTP and synaptic signaling in females via both ERα and ERβ. The estrogen dependence of LTP in females was associated with a higher threshold for both inducing potentiation and acquiring spatial information. These results indicate that the observed sexual dimorphism in hippocampal LTP reflects differences in synaptic kinase activation, including both a weaker association with NMDA receptors and a greater ERα-mediated kinase activation in response to locally produced estrogen in females. We propose that male/female differences in mechanisms and threshold for field CA1 LTP contribute to differences in encoding specific types of memories. There is good evidence for male/female differences in memory-related cognitive function, but the neurobiological basis for this sexual dimorphism is not understood. Here we describe sex differences in synaptic function in a brain area that is critical for learning spatial cues. Our results show that female rodents have higher synaptic levels of estrogen receptor α (ERα) and, in contrast to males, require membrane ERα for the activation of signaling kinases that support long-term potentiation (LTP), a form of synaptic plasticity thought to underlie learning. The additional requirement of estrogen signaling in females resulted in a higher threshold for both LTP and hippocampal field CA1-dependent spatial learning. These results describe a synaptic basis for sexual dimorphism in encoding spatial information.

Atrx deletion in neurons leads to sexually-dimorphic dysregulation of miR-137 and spatial learning and memory deficits

“…In humans, neurological disorders such as autismspectrum disorders tend to preferentially affect males rather than females, possibly due to combinatorial contributions of hormonal and genetic factors in a phenomenon known as the female protective effect [78][79][80] , and this is regularly supported with mouse models [81][82][83] . The presence of estrogen and estrogen receptor in the female brain has been shown to be neuroprotective and leads to enhanced Schaffer-collateral LTP 84 . In addition, certain X-linked genes involved in chromatin regulation (e.g.…”

Cornichon Homolog-3 (CNIH3) Modulates Spatial Memory in Female Mice

“…Several studies have reported that differences between male and female rats in evoked AMPAR/NMDAR signaling in hippocampal synapses, along with differences in the magnitude of evoked LTP, may underlie sex differences in spatial memory (Monfort et al, 2015;Qi et al, 2016). Estrous has been shown to modulate diffusion of AMPARs to the surface in female mice (Palomero-Gallagher et al, 2003;Tada et al, 2015;Bechard et al, 2018), which may underlie part of the reported importance of estrogenic mechanisms for memory in females (Cordeira et al, 2018;Frick et al, 2018;Koss et al, 2018;Wang et al, 2018;Koebele et al, 2019). However, the sex-specific role of AMPARs in memory may also be specific to the type of memory task being tested, as a study by Dachtler et al concluded that the GluA1 subunit was necessary only for male, not female, mice in fear conditioning memory, but that hippocampal GluA1 was necessary for spatial learning in both sexes (Dachtler et al, 2011).…”

Molecular Underpinnings of Estradiol-Mediated Sexual Dimorphism of Synaptic Plasticity in the Hippocampus of Rodents

“…The normal initiation of SC-LTP in females and the immediate effects of antagonist application on LTP stabilization suggest that the effects rely on local synaptic changes as opposed to ER-driven changes in gene expression at the nucleus. To confirm this, Wang et al (2018) used hippocampal slices taken from NOER (nuclear-only ER1) and MOER (membraneonly ER␣) mutant mice, which lack membrane-associated or nuclear ER␣, respectively (Pedram et al, 2013(Pedram et al, , 2014. As predicted, in slices taken from female NOER mice, LTP failed to stabilize, whereas LTP was unaffected in female MOER mice.…”

“…To investigate these possibilities, Wang et al (2018) first sought to identify the receptor subtypes that mediate E2 effects on SC-LTP. Application of ER␣-selective antagonist during theta burst stimulation (TBS) in acute brain slices permitted initial potentiation but impaired stabilization of SC-LTP in female, but not in male…”

“…Next, Wang et al (2018) investigated the relevant molecular signaling mechanisms involved in this ER␣-mediated effect. An involvement of the kinases Src and Erk1/2 is likely, given their role in the immediate component of NMDARassociated signaling and their link to ER␣ in neurons (Woolley, 2007).…”