Latent sex differences in molecular signaling that underlies excitatory synaptic potentiation in the hippocampus

Abstract

Excitatory synapses can be potentiated by chemical neuromodulators, including 17␤-estradiol (E2), or patterns of synaptic activation, as in long-term potentiation (LTP). Here, we investigated kinases and calcium sources required for acute E2-induced synaptic potentiation in the hippocampus of each sex and tested whether sex differences in kinase signaling extend to LTP. We recorded EPSCs from CA1 pyramidal cells in hippocampal slices from adult rats and used specific inhibitors of kinases and calcium sources. This revealed that, although E2 potentiates synapses to the same degree in each sex, cAMP-activated protein kinase (PKA) is required to initiate potentiation only in females. In contrast, mitogen-activated protein kinase, Src tyrosine kinase, and rho-associated kinase are required for initiation in both sexes; similarly, Ca 2ϩ /calmodulin-activated kinase II is required for expression/maintenance of E2-induced potentiation in both sexes. Calcium source experiments showed that L-type calcium channels and calcium release from internal stores are both required for E2-induced potentiation in females, whereas in males, either L-type calcium channel activation or calcium release from stores is sufficient to permit potentiation. To investigate the generalizability of a sex difference in the requirement for PKA in synaptic potentiation, we tested how PKA inhibition affects LTP. This showed that, although the magnitude of both high-frequency stimulation-induced and pairing-induced LTP is the same between sexes, PKA is required for LTP in females but not males. These results demonstrate latent sex differences in mechanisms of synaptic potentiation in which distinct molecular signaling converges to common functional endpoints in males and females.

Targeting PPARα in the rat valproic acid model of autism: focus on social motivational impairment and sex-related differences

“…The lesser deficit in social interaction of females, accompanied by the clear-cut deficit in social transmission of food preference, may be related to a different sexdependent behavioral repertoire since male rodents exhibit stronger social exploratory behaviors than females [71,72]. Sex differences in the ASD phenotype may be related to differentially regulated gene expression, synaptic function, and/or specific connectivity or patterns of brain areas' activation in males and females leading to sex-specific control of circuit activation and hence behavioral output [73,74]. For these reasons, treatments may only be effective in one sex for a specific symptom, as reported here for stereotypies, depending on the underlying mechanisms.…”

Proteomic Analysis of Brain Region and Sex-Specific Synaptic Protein Expression in the Adult Mouse Brain

“…Importantly, dendritic spine density is influenced by the estrus cycle in rodents [65]. It is well known that sex steroid hormones have an impact on synaptic function and synaptogenesis/synaptic plasticity in a sex-specific way [66][67][68][69][70]. Expression and subcellular localization of nuclear and membrane-associated steroid hormone receptors is different in male and female neurons thereby leading to different responses on hormone action.…”

Molecular mechanisms and cellular events involved in the neuroprotective actions of estradiol. Analysis of sex differences

“…Sex differences in the distribution of ERs (Bourque et al, 2011), together with a different role of ER subtypes in brain plasticity, neuroprotection and repair in male and female neurons (Bryant and Dorsa, 2010; may participate in the generation of sex differences in the neuroprotective actions of estradiol. In addition, there are differences in ER signaling in the brain of males and females (Tabatadze et al, 2015;Oberlander and Woolley, 2016;Koss et al, 2018;Jain et al, 2019;Meitzen et al, 2019;Zafer et al, 2019), which are in part mediated by epigenetic modifications in ER encoding genes (Schwarz et al, 2010;Giatti et al, 2018) and micro RNAs (Giatti et al, 2018) and are also dependent on sexually differentiated interactions with the signaling mechanisms of other neuroprotective factors, such as BDNF (Scharfman and MacLusky, 2014), IGF-1 (Munive et al, 2016) or the endocannabinoid system (Tabatadze et al, 2015), which in turn also present sex differences in the brain. All these sexually differentiated molecular mechanisms cause different responses to estradiol in the brain of male and female animals (Tabatadze et al, 2015;Munive et al, 2016;Koss et al, 2018) and may determine sex differences in the neuroprotective actions of the hormone.…”