Center for Translational Neuroscience, Department Neurobiology & Dev. Sci., University of Arkansas for Medical Sciences, Little Rock, AR, USA.
IFIBYNE, CONICET, Universidad de Buenos Aires, Buenos Aires, Argentina.
Sci Rep. 2018 Sep 3;8(1):13156. doi: 10.1038/s41598-018-31584-2.
Epigenetic mechanisms (i.e., histone post-translational modification and DNA methylation) play a role in regulation of gene expression. The pedunculopontine nucleus (PPN), part of the reticular activating system, manifests intrinsic gamma oscillations generated by voltage-dependent, high threshold N- and P/Q-type Ca channels. We studied whether PPN intrinsic gamma oscillations are affected by inhibition of histone deacetylation. We showed that, a) acute in vitro exposure to the histone deacetylation Class I and II inhibitor trichostatin A (TSA, 1 μM) eliminated oscillations in the gamma range, but not lower frequencies, b) pre-incubation with TSA (1 μM, 90-120 min) also decreased gamma oscillations, c) Ca currents (I) were reduced by TSA, especially on cells with P/Q-type channels, d) a HDAC Class I inhibitor MS275 (500 nM), and a Class IIb inhibitor Tubastatin A (150-500 nM), failed to affect gamma oscillations, e) MC1568, a HDAC Class IIa inhibitor (1 μM), blocked gamma oscillations, and f) the effects of both TSA and MC1568 were blunted by blockade of CaMKII with KN-93 (1 μM). These results suggest a cell type specific effect on gamma oscillations when histone deacetylation is blocked, suggesting that gamma oscillations through P/Q-type channels modulated by CaMKII may be linked to processes related to gene transcription.
表观遗传机制（例如组蛋白翻译后修饰和 DNA 甲基化）在基因表达调控中发挥作用。被盖核（PPN）是网状激活系统的一部分，表现出由电压依赖性、高阈值 N 和 P/Q 型 Ca 通道产生的固有伽马振荡。我们研究了 PPN 内在的伽马振荡是否受组蛋白去乙酰化抑制的影响。我们表明，a）急性离体暴露于组蛋白去乙酰化酶 I 类和 II 类抑制剂曲古抑菌素 A（TSA，1μM）消除了伽马范围内的振荡，但不影响较低频率，b）用 TSA（1μM，90-120min）预孵育也降低了伽马振荡，c）TSA 减少了 Ca 电流（I），特别是对具有 P/Q 型通道的细胞，d）HDAC I 类抑制剂 MS275（500nM）和 IIb 类抑制剂 Tubastatin A（150-500nM）均不能影响伽马振荡，e）HDAC IIa 抑制剂 MC1568（1μM）阻断了伽马振荡，f）TSA 和 MC1568 的作用均被 CaMKII 阻断剂 KN-93（1μM）削弱。这些结果表明，当组蛋白去乙酰化被阻断时，对伽马振荡有细胞类型特异性影响，表明通过 CaMKII 调制的 P/Q 型通道的伽马振荡可能与与基因转录相关的过程有关。
