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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

LTP induced by WFS (1 s-25 Hz) and MFS (1 s-50 Hz). (A) Effect of WFS in control condition (filled circles), in the presence of FIN (filled squares), LET (open squares) and FIN + LET (half-filled squares). (B) Comparison among LTP induced by HFS in control condition and by WFS in the different conditions as shown in A (one-way ANOVA, F4,44 = 42.25, p < 0.0001; Tukey’s post hoc test **p < 0.001). (C) Effect of MFS in control condition (filled circles), in the presence of FIN (filled squares), LET (open squares) and FIN + LET (half-filled squares). (D) Comparison among LTP induced by HFS in control condition and by MFS in the different conditions as shown in C (one-way ANOVA, F4,43 = 16.76, p < 0.0001; Tukey’s post hoc **p < 0.001, *p < 0.05). Note that the synthesis of DHT is mainly implied in the WFS induced LTP, while that of E2 is only involved in LTP induced by MFS.
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Figure 5: LTP induced by WFS (1 s-25 Hz) and MFS (1 s-50 Hz). (A) Effect of WFS in control condition (filled circles), in the presence of FIN (filled squares), LET (open squares) and FIN + LET (half-filled squares). (B) Comparison among LTP induced by HFS in control condition and by WFS in the different conditions as shown in A (one-way ANOVA, F4,44 = 42.25, p < 0.0001; Tukey’s post hoc test **p < 0.001). (C) Effect of MFS in control condition (filled circles), in the presence of FIN (filled squares), LET (open squares) and FIN + LET (half-filled squares). (D) Comparison among LTP induced by HFS in control condition and by MFS in the different conditions as shown in C (one-way ANOVA, F4,43 = 16.76, p < 0.0001; Tukey’s post hoc **p < 0.001, *p < 0.05). Note that the synthesis of DHT is mainly implied in the WFS induced LTP, while that of E2 is only involved in LTP induced by MFS.

Mentions: By using WFS (1 s-25 Hz) a very small LTP was induced (114.8 ± 2.2%, n = 8, 4 animals, Figure 5A) compared with that induced by HFS (Tukey’s post hoc test: WFS control vs. HFS control, p < 0.001, Figure 5B). The contribution of the neo-synthesis of DHT and/or E2 in the induction of this small LTP was examined by applying finasteride, letrozole or finasteride plus letrozole. In the presence of finasteride WFS induced a robust LTP (157.4 ± 5.9%, n = 8, 3 animals, Tukey’s post hoc test: WFS + FIN vs. WFS control, p < 0.001, Figures 5A,B), while in the presence of letrozole LTP was not different from the control one (113.7 ± 2%, n = 8, 3 animals, Tukey’s post hoc test: WFS + LET vs. WFS control, p = 0.99, WFS + LET vs. WFS + FIN, p < 0.001, Figures 5A,B). The addition of letrozole to finasteride did not modify the amplitude of LTP compared to that induced under finasteride alone (162 ± 4.2%, n = 8, 3 animals, Tukey’s post hoc test: WFS + FIN + LET vs. WFS + FIN, p = 0.98, WFS + FIN + LET vs. WFS + LET, p < 0.001, WFS + FIN + LET vs. WFS control, p < 0.001, Figures 5A,B). Conversely, MLF (1 s-50 Hz) induced LTP (196.8 ± 7.4%, n = 8, 4 animals, Figure 5C) that was not different from that induced by HFS (Tukey’s post hoc test: MFS control vs. HFS control, p = 0.99, Figure 5D). This LTP was significantly reduced in the presence of letrozole (127.9 ± 1.6%, n = 8, 3 animals, Tukey’s post hoc test: MFS + LET vs. MFS control, p < 0.001, Figures 5C,D), but it was not changed under finasteride (201.3 ± 7.7%, n = 8, 3 animals, Tukey’s post hoc test: MFS + FIN vs. MFS control, p = 0.95, Figures 5C,D). In addition, under combined application of letrozole and finasteride the amplitude of MLF-LTP (165.2 ± 2.4, n = 8, 3 animals, Figure 5C) was in-between the control and letrozole values (Tukey’s post hoc test: MFS + FIN + LET vs. MFS control, p < 0.05, MFS + FIN + LET vs. MFS + LET, p < 0.01, Figure 5D). These results suggest that for the WFS long-term response the synthesis of DHT is involved, whereas E2 does not play any role. Conversely, the synthesis of E2 is only required for the development of a full LTP by MFS.


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)

LTP induced by WFS (1 s-25 Hz) and MFS (1 s-50 Hz). (A) Effect of WFS in control condition (filled circles), in the presence of FIN (filled squares), LET (open squares) and FIN + LET (half-filled squares). (B) Comparison among LTP induced by HFS in control condition and by WFS in the different conditions as shown in A (one-way ANOVA, F4,44 = 42.25, p < 0.0001; Tukey’s post hoc test **p < 0.001). (C) Effect of MFS in control condition (filled circles), in the presence of FIN (filled squares), LET (open squares) and FIN + LET (half-filled squares). (D) Comparison among LTP induced by HFS in control condition and by MFS in the different conditions as shown in C (one-way ANOVA, F4,43 = 16.76, p < 0.0001; Tukey’s post hoc **p < 0.001, *p < 0.05). Note that the synthesis of DHT is mainly implied in the WFS induced LTP, while that of E2 is only involved in LTP induced by MFS.
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Figure 5: LTP induced by WFS (1 s-25 Hz) and MFS (1 s-50 Hz). (A) Effect of WFS in control condition (filled circles), in the presence of FIN (filled squares), LET (open squares) and FIN + LET (half-filled squares). (B) Comparison among LTP induced by HFS in control condition and by WFS in the different conditions as shown in A (one-way ANOVA, F4,44 = 42.25, p < 0.0001; Tukey’s post hoc test **p < 0.001). (C) Effect of MFS in control condition (filled circles), in the presence of FIN (filled squares), LET (open squares) and FIN + LET (half-filled squares). (D) Comparison among LTP induced by HFS in control condition and by MFS in the different conditions as shown in C (one-way ANOVA, F4,43 = 16.76, p < 0.0001; Tukey’s post hoc **p < 0.001, *p < 0.05). Note that the synthesis of DHT is mainly implied in the WFS induced LTP, while that of E2 is only involved in LTP induced by MFS.
Mentions: By using WFS (1 s-25 Hz) a very small LTP was induced (114.8 ± 2.2%, n = 8, 4 animals, Figure 5A) compared with that induced by HFS (Tukey’s post hoc test: WFS control vs. HFS control, p < 0.001, Figure 5B). The contribution of the neo-synthesis of DHT and/or E2 in the induction of this small LTP was examined by applying finasteride, letrozole or finasteride plus letrozole. In the presence of finasteride WFS induced a robust LTP (157.4 ± 5.9%, n = 8, 3 animals, Tukey’s post hoc test: WFS + FIN vs. WFS control, p < 0.001, Figures 5A,B), while in the presence of letrozole LTP was not different from the control one (113.7 ± 2%, n = 8, 3 animals, Tukey’s post hoc test: WFS + LET vs. WFS control, p = 0.99, WFS + LET vs. WFS + FIN, p < 0.001, Figures 5A,B). The addition of letrozole to finasteride did not modify the amplitude of LTP compared to that induced under finasteride alone (162 ± 4.2%, n = 8, 3 animals, Tukey’s post hoc test: WFS + FIN + LET vs. WFS + FIN, p = 0.98, WFS + FIN + LET vs. WFS + LET, p < 0.001, WFS + FIN + LET vs. WFS control, p < 0.001, Figures 5A,B). Conversely, MLF (1 s-50 Hz) induced LTP (196.8 ± 7.4%, n = 8, 4 animals, Figure 5C) that was not different from that induced by HFS (Tukey’s post hoc test: MFS control vs. HFS control, p = 0.99, Figure 5D). This LTP was significantly reduced in the presence of letrozole (127.9 ± 1.6%, n = 8, 3 animals, Tukey’s post hoc test: MFS + LET vs. MFS control, p < 0.001, Figures 5C,D), but it was not changed under finasteride (201.3 ± 7.7%, n = 8, 3 animals, Tukey’s post hoc test: MFS + FIN vs. MFS control, p = 0.95, Figures 5C,D). In addition, under combined application of letrozole and finasteride the amplitude of MLF-LTP (165.2 ± 2.4, n = 8, 3 animals, Figure 5C) was in-between the control and letrozole values (Tukey’s post hoc test: MFS + FIN + LET vs. MFS control, p < 0.05, MFS + FIN + LET vs. MFS + LET, p < 0.01, Figure 5D). These results suggest that for the WFS long-term response the synthesis of DHT is involved, whereas E2 does not play any role. Conversely, the synthesis of E2 is only required for the development of a full LTP by MFS.

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