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.
Highlights
Growing evidences show that synaptic plasticity may be rapidly modulated in different areas of the brain by sex steroids like 17β-estradiol (E2), testosterone (T) and 5αdihydrotestosterone (DHT), either produced in the gonads or locally synthesised in the brain [1,2,3,4,5,6]
Since it has been shown that the sex neurosterogenesis may be driven by synaptic stimulation involving Ca2+ influx through N-methyl-D aspartate receptor (NMDAR) [11,12,13,14,26,27], our main purpose was to understand whether and how synthesis of estrogenic and androgenic neurosteroids can be associated with activity dependent induction of NMDAR mediated long-term potentiation (LTP) and long-term depression (LTD) in the medial vestibular nucleus (MVN)
We know by our previous field potential recordings that the local synthesis of E2 is implied in LTP induced by afferent high frequency stimulation (HFS) in the MVN and hippocampus CA1 area [28,29]
Summary
Growing evidences show that synaptic plasticity may be rapidly modulated in different areas of the brain by sex steroids like 17β-estradiol (E2), testosterone (T) and 5αdihydrotestosterone (DHT), either produced in the gonads or locally synthesised in the brain [1,2,3,4,5,6]. We hypothesised that in the vestibular neurons the direction of the long-term effects in response to different patterns of afferent stimulation is due to the characteristic of the stimulus that may activate the estrogenic or androgenic pathway by facilitating the conversion of T into E2 for LTP, or into DHT for LTD To demonstrate this hypothesis, we designed this whole cell patch study in which, according to our recent finding [30], we induced LTP or LTD in the MVN neurons by varying the pattern (inter-burst interval and burst number) of high frequency burst stimulation, and we assessed the influence of androgenic and/or estrogenic neurosteroids on these opposite long-term effects by using either the antagonists of ARs and ERs or inhibitors of the DHT and E2 synthesising enzymes. Since MVN synaptic changes like LTP and LTD play a role in visuo-vestibular calibration and vestibular compensation [31,32] in response to different afferent signals, it would be interesting to find out the role of different sex neurosteroids in determining the sign of long-term changes and gain insight into their possible importance in adaptive vestibular overloading and pathological condition
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
