17β-estradiol does not have a direct effect on the function of striatal cholinergic interneurons in adult mice in vitro

Abstract

The striatum is an essential component of the basal ganglia that is involved in motor control, action selection and motor learning. The pathophysiological changes of the striatum are present in several neurological and psychiatric disorder including Parkinson’s and Huntington’s diseases. The striatal cholinergic neurons are the main regulators of striatal microcircuitry. It has been demonstrated that estrogen exerts various effects on neuronal functions in dopaminergic and medium spiny neurons (MSN), however little is known about how the activity of cholinergic interneurons are influenced by estrogens. In this study we examined the acute effect of 17β-estradiol on the function of striatal cholinergic neurons in adult mice in vitro. We also tested the effect of estrus cycle and sex on the spontaneous activity of cholinergic interneurons in the striatum. Our RNAscope experiments showed that ERα, ERβ, and GPER1 receptor mRNAs are expressed in some striatal cholinergic neurons at a very low level. In cell-attached patch clamp experiments, we found that a high dose of 17β-estradiol (100 nM) affected the spontaneous firing rate of these neurons only in old males. Our findings did not demonstrate any acute effect of a low concentration of 17β-estradiol (100 pM) or show any association of estrus cycle or sex with the activity of striatal cholinergic neurons. Although estrogen did not induce changes in the intrinsic properties of neurons, indirect effects via modulation of the synaptic inputs of striatal cholinergic interneurons cannot be excluded.

Cholinergic interneurons in the shell region of the nucleus accumbens regulate binge alcohol consumption: A chemogenetic and genetic lesion study

“…Moreover, it is widely recognized that females generally experience accelerated addiction development and encounter greater challenges in achieving abstinence (Calipari et al., 2017; Fattore et al., 2008; Towers et al., 2021). While estrogen, a female sex hormone, is known to play a substantial role in the mechanisms underlying addiction processes, little is known about how the activity of cholinergic interneurons is influenced by estrogens or changes in levels of sex‐steroid hormones across the menstrual cycle (Calipari et al., 2017; Crabbe et al., 2009; Fattore et al., 2008; Hwa et al., 2011; Kovesdi et al., 2022; Sneddon et al., 2019; Strong et al., 2010; Towers et al., 2021). Although our study did not include female subjects, given that D1‐ and D2‐MSNs are downstream targets of cholinergic interneurons in the NAc (Cachope et al., 2012; Kolpakova et al., 2022) and modulation of their activities affects alcohol consumption in both males and females (Strong et al., 2020), we hypothesize that chemogenetic and/or genetic manipulation of cholinergic interneurons would exert similar effects on alcohol consumption in females.…”

Sex differences in the distribution and density of regulatory interneurons in the striatum

“…The mechanisms underlying these differential patterns of interneuron density and distribution remain to be elucidated but are likely to involve sexually dimorphic modulation of developmental processes. Of note, estrogen receptors are expressed on both cholinergic (Almey et al, 2012; Kövesdi et al, 2022) and GABAergic interneurons (Almey et al, 2016), providing a potential mechanism for sex hormones to regulate interneuron function. These findings represent a starting point for future work analyzing the impact of these differences on sex dependent outcomes in both normal basal ganglia function and in the pathophysiology of a range of neuropsychiatric conditions, such as TS and ASD.…”

Sex differences in the distribution and density of regulatory interneurons in the striatum

“…The mechanisms underlying these differential patterns of interneuron density and distribution remain to be elucidated but are likely to involve sexually dimorphic modulation of developmental processes. Of note, ERs are expressed on both cholinergic ( Almey et al, 2012 ; Kövesdi et al, 2022 ) and GABAergic interneurons ( Almey et al, 2016 ), providing a potential mechanism for sex hormones to regulate interneuron function. These findings represent a starting point for future work analyzing the impact of these differences on sex dependent outcomes in both normal basal ganglia function and in the pathophysiology of a range of neuropsychiatric conditions, such as TS and autism spectrum disorders.…”