Sex Differences in Molecular Signaling at Inhibitory Synapses in the Hippocampus

Abstract

The possibility that mechanisms of synaptic modulation differ between males and females has far-reaching implications for understanding brain disorders that vary between the sexes. We found recently that 17␤-estradiol (E2) acutely suppresses GABAergic inhibition in the hippocampus of female rats through a sex-specific estrogen receptor ␣ (ER␣), mGluR, and endocannabinoid-dependent mechanism. Here, we define the intracellular signaling that links ER␣, mGluRs, and endocannabinoids in females and identify where in this pathway males and females differ. Using a combination of whole-cell patch-clamp recording and biochemical analyses in hippocampal slices from young adult rats, we show that E2 acutely suppresses inhibition in females through mGluR1 stimulation of phospholipase C, leading to inositol triphosphate (IP 3 ) generation, activation of the IP 3 receptor (IP 3 R), and postsynaptic endocannabinoid release, likely of anandamide. Analysis of sex differences in this pathway showed that E2 stimulates a much greater increase in IP 3 levels in females than males, whereas the group I mGluR agonist DHPG increases IP 3 levels equivalently in each sex. Coimmunoprecipitation showed that ER␣-mGluR1 and mGluR1-IP 3 R complexes exist in both sexes but are regulated by E2 only in females. Independently of E2, a fatty acid amide hydrolase inhibitor, which blocks breakdown of anandamide, suppressed Ͼ50% of inhibitory synapses in females with no effect in males, indicating tonic endocannabinoid release in females that is absent in males. Together, these studies demonstrate sex differences in both E2-dependent and E2-independent regulation of the endocannabinoid system and suggest that manipulation of endocannabinoids in vivo could affect physiological and behavioral responses differently in each sex.

Estradiol impacts the endocannabinoid system in female rats to influence behavioral and structural responses to cocaine

“…Presumably it is through this mechanism that estradiol elevates AEA to elicit anxiolytic effects in female rats, which are blocked with a CB1R antagonist (Hill et al, 2007). Moreover, this nuclear action of estradiol converges with membrane actions at the same functional endpoint to increase AEA (Huang and Woolley, 2012; Tabatadze et al, 2015). These findings parallel other biological systems, where both membrane and nuclear ERs work cooperatively to control various physiological processes (Levin, 2014, 2005; Pedram et al, 2016).…”

“…Physiological concentrations of estradiol rapidly stimulate AEA release from cultured human endothelial cells through surface membrane estrogen receptors (Maccarrone et al, 2002). Furthermore, in female rat hippocampal neurons membrane-localized ERα couples to mGluR1a, promoting AEA activation of CB1R, and leading to an attenuation of GABAergic neurotransmission (Huang and Woolley, 2012; Tabatadze et al, 2015). Coupling of ERs to mGluRs is in fact observed throughout the female nervous system, though the exact pairing of ERs and mGluRs is brain-region dependent.…”

PTEN deletion increases hippocampal granule cell excitability in male and female mice

“…The differences were evident in both control and KO cells, indicating that the dimorphism is a natural property of the cells, and not specific to PTEN deletion. There is precedent for the observation, with work by Woolley and colleagues showing sex differences in the mechanisms by which estradiol regulates both glutamatergic (Oberlander and Woolley, 2016) and GABAergic (Huang and Woolley, 2012; Tabatadze et al, 2015) transmission of hippocampal CA1 pyramidal cells. Although less extensively studied, estradiol has also been found to regulate granule cell spine density (Miranda et al, 1999; Bender et al, 2010; Hojo et al, 2015).…”

Depression in midlife women

“…The complexes of ERα, glutamate receptor and IP3R are present in both sexes, but are regulated by oestradiol only in females (30).…”