Synaptic Long-Term Potentiation and Depression in the Rat Medial Vestibular Nuclei Depend on Neural Activation of Estrogenic and Androgenic Signals

Abstract

Estrogenic and androgenic steroids can be synthesised in the brain and rapidly modulate synaptic transmission and plasticity through direct interaction with membrane receptors for estrogens (ERs) and androgens (ARs). We used whole cell patch clamp recordings in brainstem slices of male rats to explore the influence of ER and AR activation and local synthesis of 17β-estradiol (E2) and 5α-dihydrotestosterone (DHT) on the long-term synaptic changes induced in the neurons of the medial vestibular nucleus (MVN). Long-term depression (LTD) and long-term potentiation (LTP) caused by different patterns of high frequency stimulation (HFS) of the primary vestibular afferents were assayed under the blockade of ARs and ERs or in the presence of inhibitors for enzymes synthesizing DHT (5α-reductase) and E2 (P450-aromatase) from testosterone (T). We found that LTD is mediated by interaction of locally produced androgens with ARs and LTP by interaction of locally synthesized E2 with ERs. In fact, the AR block with flutamide prevented LTD while did not affect LTP, and the blockade of ERs with ICI 182,780 abolished LTP without influencing LTD. Moreover, the block of P450-aromatase with letrozole not only prevented the LTP induction, but inverted LTP into LTD. This LTD is likely due to the local activation of androgens, since it was abolished under blockade of ARs. Conversely, LTD was still induced in the presence of finasteride the inhibitor of 5α-reductase demonstrating that T is able to activate ARs and induce LTD even when DHT is not synthesized. This study demonstrates a key and opposite role of sex neurosteroids in the long-term synaptic changes of the MVN with a specific role of T-DHT for LTD and of E2 for LTP. Moreover, it suggests that different stimulation patterns can lead to LTD or LTP by specifically activating the enzymes involved in the synthesis of androgenic or estrogenic neurosteroids.

Acute inhibition of estradiol synthesis impacts vestibulo-ocular reflex adaptation and cerebellar long-term potentiation in male rats

“…In addition, a recent model (Menzies et al 2010) indicates that the "transfer" of motor memory may occur immediately after memory encoding, which is detectable within minutes after the start of the conditioning training. Finally, our previous investigations in vestibular nuclei have demonstrated that locally synthesized E2 is essential in vestibular LTP and more importantly, that LTZ inverts LTP into LTD (Grassi et al 2009b;Scarduzio et al 2013). …”

“…The modulatory role of neurosteroid E2 on synaptic plasticity has been demonstrated in vestibular nuclei, basal ganglia and hippocampus by acute as well as long-lasting inhibition of the E2 pathway, which impairs LTP induction (Grassi et al 2009a(Grassi et al , b, 2010(Grassi et al , 2012Pettorossi et al 2013;Scarduzio et al 2013;Vierk et al 2012Vierk et al , 2014. Consistent with these findings, it has been shown that acute inhibition of E2 synthesis also exerts rapid effects on spatial learning, working memory and fear extinction (Alejandre-Gomez et al 2007;Graham and Milad 2014;Moradpour et al 2006).…”

Sex differences in drug addiction and response to exercise intervention: From human to animal studies

“…Animal studies also showed sex differences in a variety of substances, but the sex-bias effects of exercise on the treatment of some drug addiction cases have been controversial (Cosgrove et al , 2002; Peterson et al , 2014; Smith et al , 2011; Smith et al , 2012; Thanos et al , 2010; Ehringer et al , 2009; Sanchez et al , 2014; Zlebnik et al , 2014b; Zhou et al , 2014). While there is no clear reason why men and women face drug addiction differently, extensive studies showed that sex hormones play critical roles in synaptic plasticity, neurogenesis and neurotransmitter systems which might be part of underlying mechanisms of drug addiction (Scarduzio et al , 2013; Li et al , 2011; Galea et al , 2014; Barth et al , 2015; Wetherington, 2010). As recently highlighted in Nature, men and women often have different profiles of drug safety and treatment efficacy (Pollitzer, 2013), we predict that men may experience different effects from exercises treating drug addiction compared to women.…”

Neurosteroids increase tonic GABAergic inhibition in the lateral section of the central amygdala in mice

“…Inhibition of the synthesis of neurosteroids with finasteride, a specific inhibitor of the 5␣-reductase (Finn et al 2006;Scarduzio et al 2013), led to a decrease in the tonic GABAergic current in CeAl neurons. Although the bath application of finasteride does not reveal the cellular source of the neurosteroids, the observed effect indicates that there is an ongoing local neurosteroid synthesis.…”

“…To test whether or not the inhibition of biosynthesis of neurosteroids would affect tonic GABAergic inhibition, we bath applied finasteride, a specific inhibitor of the 5␣-reductase (Finn et al 2006;Scarduzio et al 2013). Finasteride application induced a trend toward an increased IPSC decay half-width (control: 14.48 Ϯ 2.33 ms, finasteride: 21 Ϯ 1.84 ms; P ϭ 0.0522; n ϭ 5), which, however, was not significant.…”