Department of Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
Neurobiol Learn Mem. 2012 May;97(4):409-17. doi: 10.1016/j.nlm.2012.03.005. Epub 2012 Mar 20.
Epigenetic regulation of chromatin structure is an essential molecular mechanism that contributes to the formation of synaptic plasticity and long-term memory (LTM). An important regulatory process of chromatin structure is acetylation and deacetylation of histone proteins. Inhibition of histone deacetylase (HDAC) increases acetylation of histone proteins and facilitate learning and memory. Nitric oxide (NO) signaling pathway has a role in synaptic plasticity, LTM and regulation of histone acetylation. We have previously shown that NO signaling pathway is required for contextual fear conditioning. The present study investigated the effects of systemic administration of the HDAC inhibitor sodium butyrate (NaB) on fear conditioning in neuronal nitric oxide synthase (nNOS) knockout (KO) and wild type (WT) mice. The effect of single administration of NaB on total H3 and H4 histone acetylation in hippocampus and amygdala was also investigated. A single administration of NaB prior to fear conditioning (a) rescued contextual fear conditioning of nNOS KO mice and (b) had long-term (weeks) facilitatory effect on the extinction of cued fear memory of WT mice. The facilitatory effect of NaB on extinction of cued fear memory of WT mice was confirmed in a study whereupon NaB was administered during extinction. Results suggest that (a) the rescue of contextual fear conditioning in nNOS KO mice is associated with NaB-induced increase in H3 histone acetylation and (b) the accelerated extinction of cued fear memory in WT mice is associated with NaB-induced increase in H4 histone acetylation. Hence, a single administration of HDAC inhibitor may rescue NO-dependent cognitive deficits and afford a long-term accelerating effect on extinction of fear memory of WT mice.
染色质结构的表观遗传调控是形成突触可塑性和长时记忆（LTM）的重要分子机制。染色质结构的一个重要调控过程是组蛋白蛋白的乙酰化和去乙酰化。组蛋白去乙酰化酶（HDAC）的抑制可增加组蛋白蛋白的乙酰化，并促进学习和记忆。一氧化氮（NO）信号通路在突触可塑性、LTM 和组蛋白乙酰化的调节中起作用。我们之前已经表明，NO 信号通路是情境性恐惧条件反射所必需的。本研究探讨了系统给予组蛋白去乙酰化酶抑制剂丁酸钠（NaB）对神经元型一氧化氮合酶（nNOS）敲除（KO）和野生型（WT）小鼠恐惧条件反射的影响。还研究了单次给予 NaB 对海马和杏仁核中总 H3 和 H4 组蛋白乙酰化的影响。在恐惧条件反射之前单次给予 NaB （a）挽救了 nNOS KO 小鼠的情境性恐惧条件反射，（b）对 WT 小鼠条件性恐惧记忆的消退具有长期（数周）促进作用。在 NaB 在消退期间给予的研究中，证实了 NaB 对 WT 小鼠条件性恐惧记忆消退的促进作用。结果表明，（a）nNOS KO 小鼠情境性恐惧条件反射的挽救与 NaB 诱导的 H3 组蛋白乙酰化增加有关，（b）WT 小鼠条件性恐惧记忆消退的加速与 NaB 诱导的 H4 组蛋白乙酰化增加有关。因此，单次给予 HDAC 抑制剂可挽救与 NO 相关的认知缺陷，并对 WT 小鼠的恐惧记忆消退产生长期加速作用。
