Acetylation-Mediated Suppression of Transcription-Independent Memory: Bidirectional Modulation of Memory by Acetylation

Abstract

Learning induced changes in protein acetylation, mediated by histone acetyl transferases (HATs), and the antagonistic histone deacetylases (HDACs) play a critical role in memory formation. The status of histone acetylation affects the interaction between the transcription-complex and DNA and thus regulates transcription-dependent processes required for long-term memory (LTM). While the majority of studies report on the role of elevated acetylation in memory facilitation, we address the impact of both, increased and decreased acetylation on formation of appetitive olfactory memory in honeybees. We show that learning-induced changes in the acetylation of histone H3 at aminoacid-positions H3K9 and H3K18 exhibit distinct and different dynamics depending on the training strength. A strong training that induces LTM leads to an immediate increase in acetylation at H3K18 that stays elevated for hours. A weak training, not sufficient to trigger LTM, causes an initial increase in acetylation at H3K18, followed by a strong reduction in acetylation at H3K18 below the control group level. Acetylation at position H3K9 is not affected by associative conditioning, indicating specific learning-induced actions on the acetylation machinery. Elevating acetylation levels by blocking HDACs after conditioning leads to an improved memory. While memory after strong training is enhanced for at least 2 days, the enhancement after weak training is restricted to 1 day. Reducing acetylation levels by blocking HAT activity after strong training leads to a suppression of transcription-dependent LTM. The memory suppression is also observed in case of weak training, which does not require transcription processes. Thus, our findings demonstrate that acetylation-mediated processes act as bidirectional regulators of memory formation that facilitate or suppress memory independent of its transcription-requirement.

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

“…To confirm the different actions of the used HAT inhibitors in honeybees, we measured the levels of H3K9ac and H3K18ac after injection of garcinol or C646. We applied C646 (10 mM) and garcinol (60 mM) at concentrations and time points that have been used previously (Bowers et al 2010;Federman et al 2012;Merschbaecher et al 2012). Two hours after injection we quantified the relative amount of H3, H3K9ac, and H3K18ac in each of the brains by using the ELISA technique (Fig.…”

“…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.…”

“…Foragers were sampled at leaving the hive. After immobilization on ice, the bees were mounted in plastic tubes that allow free movement of the antennae and mouthparts (Grünbaum and Müller 1998;Merschbaecher et al 2012). Mounted bees were collectively kept in a dark humidity chamber at a relative humidity of 70% at 20˚C-25˚C.…”

“…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.…”

“…Interestingly, manipulation of acetylation-dependent processes by the HAT inhibitor garcinol also affects transient memory in honeybees (Merschbaecher et al 2012). This transient memory has been shown to be insensitive to the transcription blocker actinomycin D (Grünbaum and Müller 1998;Wüstenberg et al 1998).…”