Modulatory role of androgenic and estrogenic neurosteroids in determining the direction of synaptic plasticity in the CA1 hippocampal region of male rats

Abstract

Estrogenic and androgenic neurosteroids can rapidly modulate synaptic plasticity in the brain through interaction with membrane receptors for estrogens (ERs) and androgens (ARs). We used electrophysiological recordings in slices of young and adolescent male rats to explore the influence of sex neurosteroids on synaptic plasticity in the CA1 hippocampal region, by blocking ARs or ERs during induction of long‐term depression (LTD) and depotentiation (DP) by low‐frequency stimulation (LFS) and long‐term potentiation (LTP) by high‐frequency stimulation (HFS). We found that LTD and DP depend on ARs, while LTP on ERs in both age groups. Accordingly, the AR blocker flutamide affected induction of LTD reverting it into LTP, and prevented DP, while having no effect on HFS‐dependent LTP. Conversely, ER blockade with ICI 182,780 (ICI) markedly reduced LTP, but did not influence LTD and DP. However, the receptor blockade did not affect the maintenance of either LTD or LTP. Moreover, we found that similar to LTP and LTD induced in control condition, the LTP unveiled by flutamide during LFS and residual LTP induced by HFS under ICI depended on N‐methyl‐d aspartate receptor (NMDAR) activation. Furthermore, as the synaptic paired‐pulse facilitation (PPF) was not affected by either AR or ER blockade, we suggest that sex neurosteroids act primarily at a postsynaptic level. This study demonstrates for the first time the crucial role of estrogenic and androgenic neurosteroids in determining the sign of hippocampal synaptic plasticity in male rat and the activity‐dependent recruitment of androgenic and estrogenic pathways leading to LTD and LTP, respectively.

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

“…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).…”

“…These results are supported by previous data showing the rapid effects of inhibition of aromatase on synaptic LTP in other systems. Indeed, in hippocampus and striatum the same LTZ dose we used here prevented or remarkably reduced LTP, while in vestibular nuclei LTP was inverted in LTD without affecting the basal synaptic responses and LTD (Grassi et al 2009a(Grassi et al , b, 2010(Grassi et al , 2012Pettorossi et al 2013). …”

Estradiol rapidly modulates synaptic plasticity of hippocampal neurons: Involvement of kinase networks

“…Grassi, Pettorossi and co-workers showed that under blocking of ER by ICI, an additional inhibition of AR by flutamide induced moderate LTP (upon repetitive tetanus stimulation of 4 sets of 100 Hz, 1 s) in the developing CA1 hippocampal slices from postnatal 2-3 weeks-old rats (Pettorossi et al, 2013). This means that AR may have suppressive effects on LTP.…”

“…This means that AR may have suppressive effects on LTP. Only AR antagonist, however, does not suppress LTP upon repetitive tetanus stimulation (Pettorossi et al, 2013). Suppressive effects by DHT on LTP are also suggested for CA3 mossy fiber.…”

Estrogen receptor KO mice study on rapid modulation of spines and long-term depression in the hippocampus

“…Grassi, Petorrossi and co-workers (Pettorossi et al, 2013) show that blocking androgen receptor AR by flutamide converts LTD (upon low frequency electric stimulation) to LTP in very young hippocampal slices (two to three week old) and in adolescent hippocampal slices (seven week-old). They show that blocking estrogen receptor ER by ICI suppresses LTP, but not affects LTD.…”