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. 2010 Mar 23;107(12):5605-10.
doi: 10.1073/pnas.0910578107. Epub 2010 Mar 8.

Epigenetic alterations regulate estradiol-induced enhancement of memory consolidation

Zaorui Zhao  1 , Lu Fan, Karyn M Frick
Affiliations

Epigenetic alterations regulate estradiol-induced enhancement of memory consolidation

Zaorui Zhao et al. Proc Natl Acad Sci U S A. .

Abstract

The involvement of epigenetic alterations in mediating effects of estrogens on memory is unknown. The present study determined whether histone acetylation and DNA methylation are critical for the potent estrogen 17beta-estradiol (E(2)) to enhance object recognition memory. We show that dorsal hippocampal E(2) infusion increases acetylation of dorsal hippocampal histone H3, but not H4--an effect blocked by dorsal hippocampal inhibition of ERK activation. Further, intrahippocampal inhibition of ERK activation or DNA methyltransferase (DNMT) activity blocked the memory-enhancing effects of E(2). Consistent with these effects, E(2) decreased levels of HDAC2 protein and increased DNMT expression in the dorsal hippocampus. These findings provide evidence that the beneficial effects of E(2) on memory consolidation are associated with epigenetic alterations, and suggest these can be triggered by dorsal hippocampal ERK signaling.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Histone acetylation enhances object recognition. Mice infused with TSA (16.5 mM/side, n = 10), but not vehicle (Veh; 50% ethanol, n = 5), into the dorsal hippocampus immediately after training spent significantly more time with the novel object than chance (dashed line at 15 s; *P < 0.05) 48 h later, indicating enhanced memory for the familiar object. Vehicle mice (n = 6) spent more time than chance with the novel object 24 h after infusion (*P < 0.05), suggesting that these mice can remember the familiar object at a shorter delay. Mice infused with TSA (n = 7) 3 h after training did not spend more time than chance with the novel object. Bars represent the mean ± SEM for each object.
Fig. 2.
Fig. 2.
IH E2 infusion enhances object recognition and increases dorsal hippocampal p42 ERK activation and histone H3 acetylation. (A) Immediately after training, mice received IH Veh [2-hydroxypropyl-β-cyclodextrin (HBC), n = 9] or E2 (5 μg/side, n = 5) infusion. After 48 h, mice infused with E2, but not Veh, spent more time than chance (*P < 0.05) with the novel object. Bars represent mean ± SEM for each object. Relative to Veh, IH E2 significantly increased dorsal hippocampal: (B) p42, but not p44, ERK phosphorylation 5 min after infusion (n = 5 or 6), and (C and D) histone H3 (Lys-14), but not H4 (Lys-12), acetylation 30 min after infusion (n = 6–8). IH TSA (16.5 mM/side) significantly increased dorsal hippocampal H3 and H4 acetylation 30 min after infusion. Bars represent mean ± SEM percent change from Veh (*P < 0.05, **P < 0.01 relative to Veh, set at 100%).
Fig. 3.
Fig. 3.
Inhibition of ERK by U0126 reverses E2-induced histone H3 acetylation and blocks beneficial effects of E2 on object recognition. (A) Mice received ICV infusion of Veh (HBC) or E2 (10 μg) and IH infusion of Veh (100% DMSO) or U0126 (0.5 μg/side) immediately after training. After 48 h, ICV E2 alone, but not Veh alone, significantly increased time with the novel object relative to chance (*P < 0.05); this effect was blocked by IH U0126. U0126 alone did not affect memory consolidation. Bars represent mean ± SEM for each object, n = 4–6. (B) ICV E2 increased histone H3 (Lys-14) acetylation 1.8-fold relative to Veh 30 min after infusion; IH U0126 infusion blocked this effect. (C) ICV E2 significantly increased histone H3 (Lys-9,14) acetylation relative to Veh (*P < 0.05); IH U0126 infusion blocked this effect (#P < 0.05 relative to ICV E2). (D) Neither E2 nor U0126 altered H4 acetylation. Bars represent mean ± SEM percent change from Veh (100%). n = 5 or 6 in B–D.
Fig. 4.
Fig. 4.
Dorsal hippocampal HDAC1 and HDAC2 mRNA (A and C) and protein (B and D) expression after IH E2 (n = 4–9). (A) Relative to Veh, HDAC1 mRNA expression was significantly increased 15 min after IH E2 infusion (5 μg/side), and decreased 180 min after infusion (**P < 0.01). (B) HDAC1 protein levels were not significantly affected by E2, but tended to decrease 1 h after infusion. (C) Although not significant, HDAC2 mRNA expression was decreased from 15 to 180 min after IH E2 infusion. (D) HDAC2 protein expression was significantly decreased relative to Veh 4 h after IH E2 (*P < 0.05). Bars represent mean ± SEM percent change from Veh (100%).
Fig. 5.
Fig. 5.
(A) DNMT1 mRNA levels were not affected by IH E2 infusion (5 μg/side). (B and C) DNMT3A and DNMT3B mRNA was significantly increased relative to Veh 45 min after IH E2 (**P < 0.01). (D) c-fos mRNA was significantly increased relative to Veh 15 min after IH E2 (**P < 0.01). (E) DNMT1 protein was not changed by IH E2 infusion. (F) DNMT3A protein was slightly, but not significantly, increased 3 h after IH E2. (G) DNMT3B protein was significantly increased relative to Veh 4 h after IH E2 (*P < 0.05). (H) Mice receiving ICV E2 (10 μg), but not Veh (ICV HBC + IH 0.8% acetic acid), immediately after training spent significantly more time with the novel object than chance (*P < 0.05) after 48 h; this effect was blocked by IH 5-AZA (100 μg/side). Mice receiving IH 5-AZA plus ICV Veh (n = 8) immediately after training spent significantly more time with the novel object than chance (*P < 0.05) after 48 h; this effect was time limited, as infusion of IH 5-AZA plus ICV Veh 3 h after training (n = 6) did not increase time with the novel object after 48 h.
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