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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

Induction of long-term depression (LTD) by low frequency stimulation (LFS) depends on the synthesis of DHT. (A,C) Effects of LFS in the presence of different drugs. On the top of panels (A–C) averaged traces (n = 20) of fEPSPs recorded before (thin traces) and 40 min after LFS (thick traces) in different experimental conditions. Graphs in this and following figures report mean ± SEM (n = number of slices) of the fEPSP slope evaluated within 2-min interval and expressed as a percentage of the baseline. The gray bars show the drug infusion time and the black bars the LFS delivering time. (A) Effect of LFS in control condition (filled circles), under finasteride (FIN, filled squares) and 50 nM DHT (open circles). (B) Effect of LFS in control condition (filled circles), under FIN + 50 nM DHT (open circles), FIN + 10 nM DHT (filled triangles) and FIN + 50 nM T (open triangles). (C) Effect of LFS in control condition (filled circles), under FIN (filled squares), letrozole (LET, open circles) and FIN + LET (half-filled squares). (D) Comparison of the fEPSP changes induced by high frequency stimulation (HFS) in control condition and by LFS under different drugs as shown in (A–C). In this and following bar charts data represent mean ± SEM of the fEPSP slope (% of the baseline). Comparisons among long-term potentiation (LTP) (one-way analysis of variance (ANOVA), F8,72 = 54.2, p < 0.0001; Tukey’s post hoc test, **p < 0.001; n.s. = no significant) and LTD (one-way ANOVA, F3,29 = 0.2, p = 0.85). Note that without synthesis of DHT, LFS is able to induce a partial LTP that is not dependent on the E2 synthesis.
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Figure 1: Induction of long-term depression (LTD) by low frequency stimulation (LFS) depends on the synthesis of DHT. (A,C) Effects of LFS in the presence of different drugs. On the top of panels (A–C) averaged traces (n = 20) of fEPSPs recorded before (thin traces) and 40 min after LFS (thick traces) in different experimental conditions. Graphs in this and following figures report mean ± SEM (n = number of slices) of the fEPSP slope evaluated within 2-min interval and expressed as a percentage of the baseline. The gray bars show the drug infusion time and the black bars the LFS delivering time. (A) Effect of LFS in control condition (filled circles), under finasteride (FIN, filled squares) and 50 nM DHT (open circles). (B) Effect of LFS in control condition (filled circles), under FIN + 50 nM DHT (open circles), FIN + 10 nM DHT (filled triangles) and FIN + 50 nM T (open triangles). (C) Effect of LFS in control condition (filled circles), under FIN (filled squares), letrozole (LET, open circles) and FIN + LET (half-filled squares). (D) Comparison of the fEPSP changes induced by high frequency stimulation (HFS) in control condition and by LFS under different drugs as shown in (A–C). In this and following bar charts data represent mean ± SEM of the fEPSP slope (% of the baseline). Comparisons among long-term potentiation (LTP) (one-way analysis of variance (ANOVA), F8,72 = 54.2, p < 0.0001; Tukey’s post hoc test, **p < 0.001; n.s. = no significant) and LTD (one-way ANOVA, F3,29 = 0.2, p = 0.85). Note that without synthesis of DHT, LFS is able to induce a partial LTP that is not dependent on the E2 synthesis.

Mentions: In control condition LFS induced LTD of synaptic transmission reducing the fEPSP to 73.3 ± 3.4% (n = 9, 4 animals, Figures 1A,D). The application of finasteride did not change the baseline (pre-drug 100.6 ± 0.6% vs. post-drug 101.1 ± 0.4%, n = 8, 3 animals, Student’s t test, p = 0.51, Figure 1A), but it fully prevented LFS-LTD. A partial LTP was induced instead, since LFS enhanced the fEPSP to 148 ± 4.5% (n = 8, Figures 1A,D). This potentiation was significantly smaller than the LTP normally induced by HFS (Tukey’s post hoc test, LFS + FIN vs. HFS control: p < 0.001, Figure 1D). Moreover, finasteride applied following LFS-LTD induction had no effect (pre-drug 73.1 ± 4.6% vs. post-drug 73.7 ± 4.3%, n = 4, 2 animals, Student’s t test, p = 0.39, data not shown).


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)

Induction of long-term depression (LTD) by low frequency stimulation (LFS) depends on the synthesis of DHT. (A,C) Effects of LFS in the presence of different drugs. On the top of panels (A–C) averaged traces (n = 20) of fEPSPs recorded before (thin traces) and 40 min after LFS (thick traces) in different experimental conditions. Graphs in this and following figures report mean ± SEM (n = number of slices) of the fEPSP slope evaluated within 2-min interval and expressed as a percentage of the baseline. The gray bars show the drug infusion time and the black bars the LFS delivering time. (A) Effect of LFS in control condition (filled circles), under finasteride (FIN, filled squares) and 50 nM DHT (open circles). (B) Effect of LFS in control condition (filled circles), under FIN + 50 nM DHT (open circles), FIN + 10 nM DHT (filled triangles) and FIN + 50 nM T (open triangles). (C) Effect of LFS in control condition (filled circles), under FIN (filled squares), letrozole (LET, open circles) and FIN + LET (half-filled squares). (D) Comparison of the fEPSP changes induced by high frequency stimulation (HFS) in control condition and by LFS under different drugs as shown in (A–C). In this and following bar charts data represent mean ± SEM of the fEPSP slope (% of the baseline). Comparisons among long-term potentiation (LTP) (one-way analysis of variance (ANOVA), F8,72 = 54.2, p < 0.0001; Tukey’s post hoc test, **p < 0.001; n.s. = no significant) and LTD (one-way ANOVA, F3,29 = 0.2, p = 0.85). Note that without synthesis of DHT, LFS is able to induce a partial LTP that is not dependent on the E2 synthesis.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4591489&req=5

Figure 1: Induction of long-term depression (LTD) by low frequency stimulation (LFS) depends on the synthesis of DHT. (A,C) Effects of LFS in the presence of different drugs. On the top of panels (A–C) averaged traces (n = 20) of fEPSPs recorded before (thin traces) and 40 min after LFS (thick traces) in different experimental conditions. Graphs in this and following figures report mean ± SEM (n = number of slices) of the fEPSP slope evaluated within 2-min interval and expressed as a percentage of the baseline. The gray bars show the drug infusion time and the black bars the LFS delivering time. (A) Effect of LFS in control condition (filled circles), under finasteride (FIN, filled squares) and 50 nM DHT (open circles). (B) Effect of LFS in control condition (filled circles), under FIN + 50 nM DHT (open circles), FIN + 10 nM DHT (filled triangles) and FIN + 50 nM T (open triangles). (C) Effect of LFS in control condition (filled circles), under FIN (filled squares), letrozole (LET, open circles) and FIN + LET (half-filled squares). (D) Comparison of the fEPSP changes induced by high frequency stimulation (HFS) in control condition and by LFS under different drugs as shown in (A–C). In this and following bar charts data represent mean ± SEM of the fEPSP slope (% of the baseline). Comparisons among long-term potentiation (LTP) (one-way analysis of variance (ANOVA), F8,72 = 54.2, p < 0.0001; Tukey’s post hoc test, **p < 0.001; n.s. = no significant) and LTD (one-way ANOVA, F3,29 = 0.2, p = 0.85). Note that without synthesis of DHT, LFS is able to induce a partial LTP that is not dependent on the E2 synthesis.
Mentions: In control condition LFS induced LTD of synaptic transmission reducing the fEPSP to 73.3 ± 3.4% (n = 9, 4 animals, Figures 1A,D). The application of finasteride did not change the baseline (pre-drug 100.6 ± 0.6% vs. post-drug 101.1 ± 0.4%, n = 8, 3 animals, Student’s t test, p = 0.51, Figure 1A), but it fully prevented LFS-LTD. A partial LTP was induced instead, since LFS enhanced the fEPSP to 148 ± 4.5% (n = 8, Figures 1A,D). This potentiation was significantly smaller than the LTP normally induced by HFS (Tukey’s post hoc test, LFS + FIN vs. HFS control: p < 0.001, Figure 1D). Moreover, finasteride applied following LFS-LTD induction had no effect (pre-drug 73.1 ± 4.6% vs. post-drug 73.7 ± 4.3%, n = 4, 2 animals, Student’s t test, p = 0.39, data not shown).

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