Sex-specific regulation of inhibition and network activity by local aromatase in the mouse hippocampus

Abstract

Cognitive function relies on a balanced interplay between excitatory and inhibitory neurons (INs), but the impact of estradiol on IN function is not fully understood. Here, we characterize the regulation of hippocampal INs by aromatase, the enzyme responsible for estradiol synthesis, using a combination of molecular, genetic, functional and behavioral tools. The results show that CA1 parvalbumin-expressing INs (PV-INs) contribute to brain estradiol synthesis. Brain aromatase regulates synaptic inhibition through a mechanism that involves modification of perineuronal nets enwrapping PV-INs. In the female brain, aromatase modulates PV-INs activity, the dynamics of network oscillations and hippocampal-dependent memory. Aromatase regulation of PV-INs and inhibitory synapses is determined by the gonads and independent of sex chromosomes. These results suggest PV-INs are mediators of estrogenic regulation of behaviorally-relevant activity.

Sexually Dimorphic Role for Insular Perineuronal Nets in Aversion-Resistant Ethanol Consumption

“…In the rat agranular insula, approximately 32% of all PV+ neurons express estrogen receptor β (45). In addition, in the mouse hippocampus, PV interneurons have been shown to express aromatase, the enzyme that converts testosterone to E2, and blocking aromatase activity in females increased the intensity of PNNs surrounding PV interneurons (38). Interestingly, ChABC injection into the hippocampus of female mice did not (which was not certified by peer review) is the author/funder.…”

“…The copyright holder for this preprint this version posted January 28, 2023. ; https://doi.org/10.1101/2023.01.27.525899 doi: bioRxiv preprint affect inhibitory neurotransmission onto CA1 pyramidal cells, but was able to block the effect of an aromatase inhibitor on inhibitory currents, suggesting that when local E2 synthesis is intact, disruption of PNNs does not alter inhibitory activity in the female hippocampus (38). We hypothesize that estrogen in female insula could mask the effects of PNN removal on PV interneuron excitability and thus behavioral output.…”

“…This discrepancy could be due to regional differences. To add another layer of complexity, PNNs are regulated by hormones in female rats and mice (37, 38).…”

“…In addition, in the mouse hippocampus, PV interneurons have been shown to express aromatase, the enzyme that converts testosterone to E2, and blocking aromatase activity in females increased the intensity of PNNs surrounding PV interneurons (38). Interestingly, ChABC injection into the hippocampus of female mice did not affect inhibitory neurotransmission onto CA1 pyramidal cells, but was able to block the effect of an aromatase inhibitor on inhibitory currents, suggesting that when local E2 synthesis is intact, disruption of PNNs does not alter inhibitory activity in the female hippocampus (38). We hypothesize that estrogen in female insula could mask the effects of PNN removal on PV interneuron excitability and thus behavioral output.…”

Activational and organizational effects of sex hormones on hippocampal inhibition

“…In addition, activational effects of sex hormones released by the gonads after puberty exert transient and reversible actions in a sex specific manner (Arnold, 2009). Using genetically modified mice to break the link between gonadal and genetic sex, we have previously shown that neuroestrogen reduces CA1 synaptic inhibition and PV INs PNNs coverage in gonadal female mice with XX or XY sex chromosome complement (Hernández-Vivanco et al, 2022). These results suggest that female-specific neuroestrogen actions on hippocampal inhibition and PV INs PNNs are independent of the genetic sex of the brain and raise the alternative possibility that sex effects are determined by adult (activational) or neonatal (organizational) actions of gonadal hormones.…”