Sex-specific Difference of Hippocampal Synaptic Plasticity in Response to Sex Neurosteroids

Abstract

Numerous studies provide increasing evidence, which supports the ideas that every cell in the brain of males may differ from those in females due to differences in sex chromosome complement as well as in response to hormonal effects. In this study, we address the question as to whether actions of neurosteroids, thus steroids, which are synthesized and function within the brain, contribute to sex-specific hippocampal synaptic plasticity. We have previously shown that predominantly in the female hippocampus, does inhibition of the conversion of testosterone to estradiol affect synaptic transmission. In this study, we show that testosterone and its metabolite dihydrotestosterone are essential for hippocampal synaptic transmission specifically in males. This also holds true for the density of mushroom spines and of spine synapses. We obtained similar sex-dependent results using primary hippocampal cultures of male and female animals. Since these cultures originated from perinatal animals, our findings argue for sex-dependent differentiation of hippocampal neurons regarding their responsiveness to sex neurosteroids up to birth, which persist during adulthood. Hence, our in vitro findings may point to a developmental effect either directly induced by sex chromosomes or indirectly by fetal testosterone secretion during the perinatal critical period, when developmental sexual priming takes place.

Exploring the Impact of the Microbiome on Neuroactive Steroid Levels in Germ-Free Animals

“…In particular, DHP controls reproductive functions, as well as glutamatergic and GABAergic neurotransmission [24], whereas isoallopregnanolone influences the lipid bilayer model system containing cholesterol [25,26]. In the brain, androgen molecules have been shown to regulate dendritic spine maturation [27,28], behaviour [29,30], neurite growth [31], neurogenesis and neuronal survival [32], apoptosis [33] and catecholamine production [34]. To date, only one study, performed in male animals, has focused on the possible influence of the gut microbiota on neuroactive steroid levels.…”

Sex‐dependent responsiveness of hippocampal neurons to sex neurosteroids: A role of Arc/Arg3.1

“…To determine whether the local synthesis of sex steroids, namely E 2 and DHT, which were shown to induce synaptic plasticity in the hippocampus in a sex‐dependent manner, 25 are of any relevance, we additionally used finasteride to inhibit DHT synthesis, via blocking 5α‐reductase, and letrozole to inhibit E 2 synthesis, via blocking of aromatase. The doses of sex steroid synthesis blockers were adopted from previous studies, in which we tested the efficacy of the blockers 22,23,25 . Because testosterone is the substrate of both enzymes, aromatase and 5α‐reductase, 25,32 it has to be considered that the inhibitors increase testosterone levels as side effects 25 …”

“…In general, the upregulation was more pronounced after DHT than after E2 treatment. Based upon our earlier findings that inhibition of local synthesis of E 2 and DHT, respectively, results in impairment of synaptic plasticity, 24,25 we also looked at the effects of sex steroid blockers.…”

Astrocyte-Derived Thrombospondin Induces Cortical Synaptogenesis in a Sex-Specific Manner

“…Further complicating the story is the knowledge that estradiol would not be the sole compound whose synthesis would be affected by letrozole, since aromatase inhibition would make testosterone, the substrate for E2, more readily available for conversion to dihydrotestosterone (DHT) via 5α-reductase. DHT acts via androgen receptors (ARs), which have previously been shown to influence synaptic development in a sex-specific manner ( Brandt et al, 2020 ). Studies are ongoing to elucidate this mechanism more fully, as well as to establish the relevance of this process for sex differences in cortical development in vivo .…”