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Neo-synthesis of estrogenic or androgenic neurosteroids determine whether long-term potentiation or depression is induced in hippocampus of male rat.

Di Mauro M, Tozzi A, Calabresi P, Pettorossi VE, Grassi S - Front Cell Neurosci (2015)

Bottom Line: We found that LFS-LTD depends on DHT synthesis, since it was fully prevented under finasteride, an inhibitor of DHT synthesis, and rescued by exogenous DHT, while the E2 synthesis was not involved.Conversely, the full development of HFS-LTP requires the synthesis of E2, as demonstrated by the LTP reduction observed under letrozole, an inhibitor of E2 synthesis, and its full rescue by exogenous E2.Overall, these results indicate that DHT is required for converting the partial LTP into LTD whereas E2 is needed for the full expression of LTP, evidencing a key role of the neo-synthesis of sex neurosteroids in determining the direction of synaptic long-term effects.

View Article: PubMed Central - PubMed

Affiliation: Dipartimento di Medicina Sperimentale, Sezione di Fisiologia e Biochimica, Università di Perugia Perugia, Italy.

ABSTRACT
Estrogenic and androgenic steroids synthesized in the brain may rapidly modulate synaptic plasticity interacting with specific membrane receptors. We explored by electrophysiological recordings in hippocampal slices of male rat the influence of 17β-estradiol (E2) and 5α-dihydrotestosterone (DHT) neo-synthesis on the synaptic changes induced in the CA1 region. Induction of long-term depression (LTD) and depotentiation (DP) by low frequency stimulation (LFS, 15 min-1 Hz) and of long-term potentiation (LTP) by high frequency stimulation (HFS, 1 s-100 Hz), medium (MFS, 1 s-50 Hz), or weak (WFS, 1 s-25 Hz) frequency stimulation was assayed under inhibitors of enzymes converting testosterone (T) into DHT (5α-reductase) and T into E2 (P450-aromatase). We found that LFS-LTD depends on DHT synthesis, since it was fully prevented under finasteride, an inhibitor of DHT synthesis, and rescued by exogenous DHT, while the E2 synthesis was not involved. Conversely, the full development of HFS-LTP requires the synthesis of E2, as demonstrated by the LTP reduction observed under letrozole, an inhibitor of E2 synthesis, and its full rescue by exogenous E2. For intermediate stimulation protocols DHT, but not E2 synthesis, was involved in the production of a small LTP induced by WFS, while the E2 synthesis was required for the MFS-dependent LTP. Under the combined block of DHT and E2 synthesis all stimulation frequencies induced partial LTP. Overall, these results indicate that DHT is required for converting the partial LTP into LTD whereas E2 is needed for the full expression of LTP, evidencing a key role of the neo-synthesis of sex neurosteroids in determining the direction of synaptic long-term effects.

No MeSH data available.


Related in: MedlinePlus

Neo-synthesis of E2 is involved in the full development of HFS-LTP. (A,B) On the top averaged traces (n = 20) of fEPSPs recorded before (thin traces) and 40 min after HFS (thick traces) in different experimental conditions. (A) Effect of HFS in control condition (filled circles), under LET (open squares), FIN (filled squares) and LET + FIN (half-filled squares). (B) Effect of HFS in control condition (filled circles), in the presence of LET (open squares), 1 nM E2 (filled triangles), LET + 1 nM E2 (half-filled triangles) and LET + 0.5 nM E2 (open triangles). (C) Effect of HFS in control condition (filled circles) and in the presence of 50 nM DHT (open circles). (D) Comparison among LTP induced by HFS in control condition and under blockade of E2 and DHT synthesis as shown in (A) (one-way ANOVA, F3,39 = 87.7, p < 0.0001; Tukey’s post hoc test **p < 0.001, *p < 0.05). (E) Comparison among LTP induced by HFS in control condition, under exogenous DHT and E2 with or without LET (one-way ANOVA, F5,54 = 42.6, p < 0.0001; Tukey’s post hoc test **p < 0.001). Note that for the full development of HFS-LTP the synthesis of E2 is mainly requested and the block of DHT synthesis further increases LTP.
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Figure 4: Neo-synthesis of E2 is involved in the full development of HFS-LTP. (A,B) On the top averaged traces (n = 20) of fEPSPs recorded before (thin traces) and 40 min after HFS (thick traces) in different experimental conditions. (A) Effect of HFS in control condition (filled circles), under LET (open squares), FIN (filled squares) and LET + FIN (half-filled squares). (B) Effect of HFS in control condition (filled circles), in the presence of LET (open squares), 1 nM E2 (filled triangles), LET + 1 nM E2 (half-filled triangles) and LET + 0.5 nM E2 (open triangles). (C) Effect of HFS in control condition (filled circles) and in the presence of 50 nM DHT (open circles). (D) Comparison among LTP induced by HFS in control condition and under blockade of E2 and DHT synthesis as shown in (A) (one-way ANOVA, F3,39 = 87.7, p < 0.0001; Tukey’s post hoc test **p < 0.001, *p < 0.05). (E) Comparison among LTP induced by HFS in control condition, under exogenous DHT and E2 with or without LET (one-way ANOVA, F5,54 = 42.6, p < 0.0001; Tukey’s post hoc test **p < 0.001). Note that for the full development of HFS-LTP the synthesis of E2 is mainly requested and the block of DHT synthesis further increases LTP.

Mentions: In full agreement with our previous results (Grassi et al., 2011), HFS in the presence of letrozole induced LTP (129 ± 4.3%, n = 10, 4 animals, Figures 4A,B) that was significantly smaller than that obtained in the control condition (199.8 ± 7%, n = 17, 6 animals, Tukey’s post hoc test: HFS + LET vs. HFS control, p < 0.001, Figure 4D). By contrast, LTP induced under finasteride was markedly enhanced (296.5 ± 9.1%, n = 8, 3 animals, Tukey’s post hoc test: HFS + FIN vs. HFS control, p < 0.001, Figures 4A,D). In addition, the combined application of finasteride and letrozole caused LTP (165.3 ± 2.2%, n = 8, 3 animals, Figure 4A) of an amplitude that was in-between the control LTP and LTP under letrozole alone (Tukey’s post hoc test: HFS + LET + FIN vs. HFS control, p < 0.01, HFS + LET + FIN vs. HFS + LET, p < 0.01, Figures 4A,D).


Neo-synthesis of estrogenic or androgenic neurosteroids determine whether long-term potentiation or depression is induced in hippocampus of male rat.

Di Mauro M, Tozzi A, Calabresi P, Pettorossi VE, Grassi S - Front Cell Neurosci (2015)

Neo-synthesis of E2 is involved in the full development of HFS-LTP. (A,B) On the top averaged traces (n = 20) of fEPSPs recorded before (thin traces) and 40 min after HFS (thick traces) in different experimental conditions. (A) Effect of HFS in control condition (filled circles), under LET (open squares), FIN (filled squares) and LET + FIN (half-filled squares). (B) Effect of HFS in control condition (filled circles), in the presence of LET (open squares), 1 nM E2 (filled triangles), LET + 1 nM E2 (half-filled triangles) and LET + 0.5 nM E2 (open triangles). (C) Effect of HFS in control condition (filled circles) and in the presence of 50 nM DHT (open circles). (D) Comparison among LTP induced by HFS in control condition and under blockade of E2 and DHT synthesis as shown in (A) (one-way ANOVA, F3,39 = 87.7, p < 0.0001; Tukey’s post hoc test **p < 0.001, *p < 0.05). (E) Comparison among LTP induced by HFS in control condition, under exogenous DHT and E2 with or without LET (one-way ANOVA, F5,54 = 42.6, p < 0.0001; Tukey’s post hoc test **p < 0.001). Note that for the full development of HFS-LTP the synthesis of E2 is mainly requested and the block of DHT synthesis further increases LTP.
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Related In: Results  -  Collection

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Figure 4: Neo-synthesis of E2 is involved in the full development of HFS-LTP. (A,B) On the top averaged traces (n = 20) of fEPSPs recorded before (thin traces) and 40 min after HFS (thick traces) in different experimental conditions. (A) Effect of HFS in control condition (filled circles), under LET (open squares), FIN (filled squares) and LET + FIN (half-filled squares). (B) Effect of HFS in control condition (filled circles), in the presence of LET (open squares), 1 nM E2 (filled triangles), LET + 1 nM E2 (half-filled triangles) and LET + 0.5 nM E2 (open triangles). (C) Effect of HFS in control condition (filled circles) and in the presence of 50 nM DHT (open circles). (D) Comparison among LTP induced by HFS in control condition and under blockade of E2 and DHT synthesis as shown in (A) (one-way ANOVA, F3,39 = 87.7, p < 0.0001; Tukey’s post hoc test **p < 0.001, *p < 0.05). (E) Comparison among LTP induced by HFS in control condition, under exogenous DHT and E2 with or without LET (one-way ANOVA, F5,54 = 42.6, p < 0.0001; Tukey’s post hoc test **p < 0.001). Note that for the full development of HFS-LTP the synthesis of E2 is mainly requested and the block of DHT synthesis further increases LTP.
Mentions: In full agreement with our previous results (Grassi et al., 2011), HFS in the presence of letrozole induced LTP (129 ± 4.3%, n = 10, 4 animals, Figures 4A,B) that was significantly smaller than that obtained in the control condition (199.8 ± 7%, n = 17, 6 animals, Tukey’s post hoc test: HFS + LET vs. HFS control, p < 0.001, Figure 4D). By contrast, LTP induced under finasteride was markedly enhanced (296.5 ± 9.1%, n = 8, 3 animals, Tukey’s post hoc test: HFS + FIN vs. HFS control, p < 0.001, Figures 4A,D). In addition, the combined application of finasteride and letrozole caused LTP (165.3 ± 2.2%, n = 8, 3 animals, Figure 4A) of an amplitude that was in-between the control LTP and LTP under letrozole alone (Tukey’s post hoc test: HFS + LET + FIN vs. HFS control, p < 0.01, HFS + LET + FIN vs. HFS + LET, p < 0.01, Figures 4A,D).

Bottom Line: We found that LFS-LTD depends on DHT synthesis, since it was fully prevented under finasteride, an inhibitor of DHT synthesis, and rescued by exogenous DHT, while the E2 synthesis was not involved.Conversely, the full development of HFS-LTP requires the synthesis of E2, as demonstrated by the LTP reduction observed under letrozole, an inhibitor of E2 synthesis, and its full rescue by exogenous E2.Overall, these results indicate that DHT is required for converting the partial LTP into LTD whereas E2 is needed for the full expression of LTP, evidencing a key role of the neo-synthesis of sex neurosteroids in determining the direction of synaptic long-term effects.

View Article: PubMed Central - PubMed

Affiliation: Dipartimento di Medicina Sperimentale, Sezione di Fisiologia e Biochimica, Università di Perugia Perugia, Italy.

ABSTRACT
Estrogenic and androgenic steroids synthesized in the brain may rapidly modulate synaptic plasticity interacting with specific membrane receptors. We explored by electrophysiological recordings in hippocampal slices of male rat the influence of 17β-estradiol (E2) and 5α-dihydrotestosterone (DHT) neo-synthesis on the synaptic changes induced in the CA1 region. Induction of long-term depression (LTD) and depotentiation (DP) by low frequency stimulation (LFS, 15 min-1 Hz) and of long-term potentiation (LTP) by high frequency stimulation (HFS, 1 s-100 Hz), medium (MFS, 1 s-50 Hz), or weak (WFS, 1 s-25 Hz) frequency stimulation was assayed under inhibitors of enzymes converting testosterone (T) into DHT (5α-reductase) and T into E2 (P450-aromatase). We found that LFS-LTD depends on DHT synthesis, since it was fully prevented under finasteride, an inhibitor of DHT synthesis, and rescued by exogenous DHT, while the E2 synthesis was not involved. Conversely, the full development of HFS-LTP requires the synthesis of E2, as demonstrated by the LTP reduction observed under letrozole, an inhibitor of E2 synthesis, and its full rescue by exogenous E2. For intermediate stimulation protocols DHT, but not E2 synthesis, was involved in the production of a small LTP induced by WFS, while the E2 synthesis was required for the MFS-dependent LTP. Under the combined block of DHT and E2 synthesis all stimulation frequencies induced partial LTP. Overall, these results indicate that DHT is required for converting the partial LTP into LTD whereas E2 is needed for the full expression of LTP, evidencing a key role of the neo-synthesis of sex neurosteroids in determining the direction of synaptic long-term effects.

No MeSH data available.


Related in: MedlinePlus