Estradiol rapidly modulates excitatory synapse properties in a sex- and region-specific manner in rat nucleus accumbens core and caudate-putamen

Abstract

Estradiol acutely facilitates sex differences in striatum-dependent behaviors. However, little is understood regarding the underlying mechanism. In striatal regions in adult rodents, estrogen receptors feature exclusively extranuclear expression, suggesting that estradiol rapidly modulates striatal neurons. We tested the hypothesis that estradiol rapidly modulates excitatory synapse properties onto medium spiny neurons (MSNs) of two striatal regions, the nucleus accumbens core and caudate-putamen in adult female and male rats. We predicted there would be sex-specific differences in pre- and postsynaptic locus and sensitivity. We further analyzed whether MSN intrinsic properties are predictive of estrogen sensitivity. Estradiol exhibited sex-specific acute effects in the nucleus accumbens core: miniature excitatory postsynaptic current (mEPSC) frequency robustly decreased in response to estradiol in female MSNs, and mEPSC amplitude moderately increased in response to estradiol in both male and female MSNs. This increase in mEPSC amplitude is associated with MSNs featuring increased intrinsic excitability. No MSN intrinsic electrical property associated with changes in mEPSC frequency. Estradiol did not acutely modulate mEPSC properties in the caudate-putamen of either sex. This is the first demonstration of acute estradiol action on MSN excitatory synapse function. This demonstration of sex and striatal region-specific acute estradiol neuromodulation revises our understanding of sex hormone action on striatal physiology and resulting behaviors. NEW & NOTEWORTHY This study is the first to demonstrate rapid estradiol neuromodulation of glutamatergic signaling on medium spiny neurons (MSNs), the major output neuron of the striatum. These findings emphasize that sex is a significant biological variable both in MSN sensitivity to estradiol and in pre- and postsynaptic mechanisms of glutamatergic signaling. MSNs in different regions exhibit diverse responses to estradiol. Sex- and region-specific estradiol-induced changes to excitatory signaling on MSNs explain sex differences partially underlying striatum-mediated behaviors and diseases.

Estrogen receptor alpha, G‐protein coupled estrogen receptor 1, and aromatase: Developmental, sex, and region‐specific differences across the rat caudate–putamen, nucleus accumbens core and shell

“…Quantifying DHHC expression and activity across development will be necessary to test this hypothesis further. Striatal neurons are also known to be sensitive to perinatal aromatization (Bonansco et al, 2018; Cao et al, 2016), and sensitive to fluctuations in sex steroid hormones in adulthood (Krentzel, Barrett, & Meitzen, 2019; Meitzen et al, 2018; Proano, Morris, Kunz, Dorris, & Meitzen, 2018; Willett et al, 2019; Wissman, May, & Woolley, 2012), though not in gross anatomical attributes (Meitzen et al, 2011; Wong, Cao, Dorris, & Meitzen, 2016). Aromatization of testosterone to estradiol early in life may also play a role in males, though this question requires further exploration.…”

“…This relationship between aromatase and extranuclear ER expression is similar to other brain areas exhibiting known rapid estradiol signaling such as the hippocampus of rodents (Kim, Szinte, Boulware, & Frick, 2016; Oberlander & Woolley, 2016; Sato & Woolley, 2016; Tabatadze et al, 2013; Tuscher et al, 2016) and the auditory forebrain of songbirds (Ikeda et al, 2017; Krentzel et al, 2018; Krentzel, Ikeda, Oliver, Koroveshi, & Remage‐Healey, 2019; Remage‐Healey, Dong, Chao, & Schlinger, 2012; Remage‐Healey, Dong, Maidment, & Schlinger, 2011; Saldanha et al, 2000). Overall, the pattern of increased estrogen‐producing cells and a change in the phenotype of estrogen‐sensitive cells suggests that the striatum transforms in adulthood into a region targeted by rapid, neuromodulatory mechanisms of estrogenic signaling (Krentzel, Barrett, & Meitzen, 2019; Meitzen et al, 2018; Yoest, Quigley, & Becker, 2018).…”

Neural and Hormonal Control of Sexual Behavior

“…Furthermore, like in many of the regions discussed above, estrogen exposure also regulates spine density in the NAc ( 198 , 199 ). These effects seem to be region-specific within the striatum, as estrogenic effects on spine density and excitatory synaptic properties observed in the NAc were not seen in the caudate-putamen ( 197 , 198 ). The effects of gonadal hormones on NAc physiology is not limited to females, as long-term treatment with androgens in males also modulates NAc dendritic spine density ( 200 ).…”

“…VTA dopaminergic neuron basal firing rate is enhanced and more dopamine released into the NAc during behavioral estrus ( 193-195 ). Several electrophysiological properties of NAc medium spiny neurons have been reported to either vary across the estrous cycle or to be rapidly modulated by estradiol exposure ( 192 , 196 , 197 ). Furthermore, like in many of the regions discussed above, estrogen exposure also regulates spine density in the NAc ( 198 , 199 ).…”

Rapid Estrogenic and Androgenic Neurosteroids Effects in the Induction of Long-Term Synaptic Changes: Implication for Early Memory Formation

“…Neural E2 exerts an important role in LTP induction in the nucleus striatum with E2 receptors diffusely expressed in the basal ganglia (Creutz and Kritzer, 2004;Krentzel et al, 2019). Electrophysiological experiments performed in neurons of the dorsal striatum of the male rat showed that E2 synthesis and ER activation are required for the induction of LTP in both spiny projection neurons (SPNs) and cholinergic interneurons because the pharmacological inhibition of P450 aromatase or antagonism of ERs completely prevented the LTP induction of SPNs with no effect on LTD or synaptic depotentiation (Tozzi et al, 2015).…”