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.
Highlights
Long-term memory (LTM), and long-lasting synaptic changes are characterized by their dependence on protein synthesis and gene expression [1,2,3]
We demonstrate that in contrast to strong appetitive associative training, weak training leads to a delayed reduction in acetylation of H3K18 in the honeybee brain
Disregarding training strength, the reduction of protein acetylation levels suppresses memory performance. These findings support the ‘‘molecular brake pad hypothesis’’ [8] that proposes a role of learning induced acetylation-dependent processes in memory suppression in vivo
Summary
Long-term memory (LTM), and long-lasting synaptic changes are characterized by their dependence on protein synthesis and gene expression [1,2,3]. These changes in gene expression are induced by a series of conserved second messenger mediated events that change the activity of transcription factors, and gene expression [4,5,6]. Work in Aplysia and rodents demonstrated that transcriptional co-activators like CBP (CREB binding protein), p300, and the p300/CBP associated factor (PCAF) have intrinsic HAT activities, essential for gene expression underlying long-lasting neuronal plasticity [12,13,14,15,16,17]. In presence of HDAC inhibitors, subthreshold stimulation, or a weak training, is sufficient to trigger long-term facilitation (LTF) in Aplysia [13], to facilitate memory formation in crabs [18], and to enhance long-term potentiation (LTP), or memory in rodents [19,20,21,22,23,24]
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