Laboratory of regulation of functions of brain neurons, Pavlov Institute of Physiology Russian Academy of Sciences, St. Petersburg, Russia.
PLoS One. 2012;7(7):e41828. doi: 10.1371/journal.pone.0041828. Epub 2012 Jul 25.
Animals' capacities for different forms of learning do not mature simultaneously during ontogenesis but the molecular mechanisms behind the delayed development of specific types of memory are not fully understood. Mollusks are considered to be among the best models to study memory formation at the molecular level. Chromatin remodeling in developmental processes, as well as in long-term memory formation, was recently shown to play a major role. Histone acetylation is a key process in the chromatin remodeling and is regulated through the signaling cascades, for example MAPK/ERK. Previously, we found that MAPK/ERK is a key pathway in the formation of the food aversion reflex in Helix. Pretreatment with upstream ERK kinase inhibitor PD98059 prevented food avoidance learning in adult Helix. In contrast to adult snails, juveniles possess immature plasticity mechanisms of the avoidance reflex until the age of 2-3 months while the MAPK/ERK cascade is not activated after aversive learning. In the present study, we focused on the potential MAPK/ERK target--histone H3.
METHODOLOGY/PRINCIPAL FINDINGS: Here we found that a significant increase in histone H3 acetylation occurs in adult animals after learning, whereas no corresponding increase was observed in juveniles. The acetylation of histone H3 is regulated by ERK kinase, since the upstream ERK kinase inhibitor PD98059 prevented the increase of histone H3 acetylation upon learning. We found that the injection of histone deacetylase inhibitor sodium butyrate (NaB) prior to training led to induction in histone H3 acetylation and significantly ameliorated long-term memory formation in juvenile snails.
CONCLUSIONS/SIGNIFICANCE: Thus, MAPK/ERK-dependent histone H3 acetylation plays an essential role in the formation of food aversion in Helix. Dysfunction of the MAPK/ERK dependent histone H3 acetylation might determine the deficiency of avoidance behavior and long-term plasticity in juvenile animals. Stimulation of histone H3 acetylation in juvenile animals by NaB promoted avoidance plasticity.
动物在不同形式的学习中的能力在个体发生过程中不会同时成熟，但特定类型记忆发育延迟的分子机制尚不完全清楚。软体动物被认为是研究分子水平记忆形成的最佳模型之一。最近表明，染色质重塑在发育过程中以及在长期记忆形成中起着重要作用。组蛋白乙酰化是染色质重塑的关键过程，通过信号级联（例如 MAPK/ERK）进行调节。以前，我们发现 MAPK/ERK 是形成 Helix 食物厌恶反射的关键途径。用上游 ERK 激酶抑制剂 PD98059 预处理可防止成年 Helix 避免学习。与成年蜗牛不同，幼体在 2-3 个月大之前具有不成熟的回避反射可塑性机制，而 MAPK/ERK 级联在厌恶学习后不会被激活。在本研究中，我们专注于潜在的 MAPK/ERK 靶标——组蛋白 H3。
方法/主要发现：在这里，我们发现学习后成年动物中的组蛋白 H3 乙酰化显著增加，而幼体中则没有观察到相应的增加。组蛋白 H3 的乙酰化受 ERK 激酶调节，因为上游 ERK 激酶抑制剂 PD98059 可防止学习后组蛋白 H3 乙酰化的增加。我们发现，在训练前注射组蛋白去乙酰化酶抑制剂丁酸钠（NaB）会导致组蛋白 H3 乙酰化诱导，并显著改善幼蜗牛的长期记忆形成。
结论/意义：因此，MAPK/ERK 依赖性组蛋白 H3 乙酰化在 Helix 中形成食物厌恶中起关键作用。MAPK/ERK 依赖性组蛋白 H3 乙酰化功能障碍可能决定幼小动物回避行为和长期可塑性的缺乏。NaB 刺激幼体中的组蛋白 H3 乙酰化可促进回避可塑性。
