Hippocampal Histone Acetylation Regulates Object Recognition and the Estradiol-Induced Enhancement of Object Recognition

Abstract

Histone acetylation has recently been implicated in learning and memory processes, yet necessity of histone acetylation for such processes has not been demonstrated using pharmacological inhibitors of histone acetyltransferases (HATs). As such, the present study tested whether garcinol, a potent HAT inhibitor in vitro, could impair hippocampal memory consolidation and block the memory-enhancing effects of the modulatory hormone 17β-estradiol (E2). We first showed that bilateral infusion of garcinol (0.1, 1, or 10 μg/side) into the dorsal hippocampus (DH) immediately after training impaired object recognition memory consolidation in ovariectomized female mice. A behaviorally effective dose of garcinol (10 μg/side) also significantly decreased DH HAT activity. We next examined whether DH infusion of a behaviorally subeffective dose of garcinol (1 ng/side) could block the effects of DH E2 infusion on object recognition and epigenetic processes. Immediately after training, ovariectomized female mice received bilateral DH infusions of vehicle, E2 (5 μg/side), garcinol (1 ng/side), or E2 plus garcinol. Forty-eight hours later, garcinol blocked the memory-enhancing effects of E2. Garcinol also reversed the E2-induced increase in DH histone H3 acetylation, HAT activity, and levels of the de novo methyltransferase DNMT3B, as well as the E2-induced decrease in levels of the memory repressor protein histone deacetylase 2 (HDAC2). Collectively, these findings suggest that histone acetylation is critical for object recognition memory consolidation and the beneficial effects of E2 on object recognition. Importantly, this work demonstrates that the role of histone acetylation in memory processes can be studied using a HAT inhibitor.

Estradiol-induced object recognition memory consolidation is dependent on activation of mTOR signaling in the dorsal hippocampus

“…Phospho-p42 ERK levels differed significantly among the groups (F (5,24) ¼ 8.61, P , 0.001). As in our previous studies (Fernandez et al 2008;Lewis et al 2008;Fan et al 2010;Zhao et al 2010Zhao et al , 2012, E 2 significantly increased levels of (LY) (0.005 mg/side), or Rapamycin (Rap) (0.025 ng/side) immediately after training spent significantly more time than chance (dashed line at 15 sec) with the novel object 24 h later, demonstrating that these inhibitor doses did not impair object recognition at this delay. However, mice receiving 0.05 mg/side LY or 0.25 ng/side rapamycin spent no more time than chance with the novel object, suggesting that higher doses reveal a critical involvement of PI3K and mTOR signaling in object recognition memory formation.…”

“…We previously demonstrated that a single bilateral post-training infusion of 5 mg E 2 into the dorsal hippocampus enhances object recognition in young (3-mo-old) and middle-aged (17-moold) ovariectomized mice (Fernandez et al 2008;Fan et al 2010;Zhao et al 2010Zhao et al , 2012. In middle-aged females, we found that the E 2 -induced enhancement of object recognition was dependent on dorsal hippocampal ERK and PI3K activation , but in young females we have thus far only demonstrated the critical involvement of ERK (Fernandez et al 2008;Lewis et al 2008;Zhao et al 2010).…”

“…In female rodents, a single systemic injection or direct dorsal hippocampal infusion of E 2 immediately after training (i.e., posttraining) in an object recognition task significantly enhances object recognition memory consolidation (Luine et al 2003;Walf et al 2006Walf et al , 2008Fernandez et al 2008;Lewis et al 2008;Fan et al 2010;Zhao et al 2010Zhao et al , 2012. Using the ERK activation inhibitors U0126 and SL327, we recently demonstrated that activation of ERK in the dorsal hippocampus is necessary for E 2 to enhance object recognition memory in young or middle-aged ovariectomized mice (Fernandez et al 2008;Fan et al 2010).…”

Inhibition of different histone acetyltransferases (HATs) uncovers transcription-dependent and -independent acetylation-mediated mechanisms in memory formation

“…Both findings are new facets of our understanding of memory formation. Previous studies addressed the function of either garcinol or C646 in memory formation (Marek et al 2011;Merschbaecher et al 2012;Zhao et al 2012;Maddox et al 2013a,b). In mice, injection of garcinol (Maddox et al 2013a) or C646 (Maddox et al 2013b) into the amygdala impairs newly acquired as well as reactivated fear memories.…”

“…This picture is supported by studies using pharmacological tools to target different HATs and HDACs (Dekker and Haisma 2009;Bowers et al 2010;Selvi et al 2010). Focusing here on the HATs, which have been tested in different invertebrate and mammalian learning paradigms (Marek et al 2011;Merschbaecher et al 2012;Zhao et al 2012;Maddox et al 2013a,b), it has not been addressed how the different HATs (CBP, p300, PCAF, etc.) contribute to particular mechanisms in memory formation.…”