The pedunculopontine nucleus (PPN) has long been known to be part of the reticular activating system (RAS) in charge of arousal and REM sleep. We previously showed that in vitro exposure to a HDAC Class I and II mixed inhibitor (TSA), or a specific HDAC class IIa inhibitor (MC 1568), decreased PPN gamma oscillations. Given the lack of information on systemic in vivo treatments on neuronal synaptic properties, the present study was designed to investigate the systemic effect of HDAC inhibitors (HDACi) on PPN rhythmicity. Rat pups were injected (acute, single dose) with TSA (4 or 20 mg/kg), MC1568 (4 or 20 mg/kg), or MS275 (20 or 100 mg/kg). Our results show that MC1568 (20 mg/kg) reduced mean frequency of PPN oscillations at gamma band, while increasing mean input resistance (Rm) of PPN neurons. For TSA (4 and 20 mg/kg), we observed reduced mean frequency of oscillations at gamma band and increased mean Rm of PPN neurons. Systemic administration of 20 mg/kg MC1568 and TSA effects on Rm were washed out after 60 min of in vitro incubation of PPN slices, suggesting an underlying functional recovery of PPN calcium-mediated gamma band oscillations over time. In addition, at a lower dose, 4 mg/kg, MC1568 and TSA induced higher mean amplitude gamma oscillations. Blocking HDAC class I might not have deleterious effects on gamma activity, but, more importantly, the inhibition of HDAC class I (at 100 mg/kg) increased gamma band oscillations. In conclusion, the present results in vivo validate our previous findings in vitro and further expand information on the effects of HDAC inhibition on PPN rhythmicity. PPN neurons require normal activity of HDAC class IIa in order to oscillate at gamma band.

中文翻译：

---

HDAC抑制剂对体内PPN振荡活性的差异作用。

人们早已知道人脚桥骨核（PPN）是网状激活系统（RAS）的一部分，负责唤醒和REM睡眠。我们以前表明，在体外暴露于HDAC I类和II类混合抑制剂（TSA）或特定的HDAC IIa类抑制剂（MC 1568）可以降低PPNγ振荡。鉴于缺乏有关神经元突触特性的全身体内治疗的信息，本研究旨在研究HDAC抑制剂（HDACi）对PPN节律的全身作用。给大鼠幼鼠注射（急性，单剂）TSA（4或20 mg / kg），MC1568（4或20 mg / kg）或MS275（20或100 mg / kg）。我们的结果表明，MC1568（20 mg / kg）降低了γ波段PPN振荡的平均频率，同时增加了PPN神经元的平均输入电阻（Rm）。对于TSA（4和20 mg / kg），我们观察到降低了在伽马带的平均振荡频率，并增加了PPN神经元的平均Rm。PPN切片体外温育60分钟后，冲洗掉了20 mg / kg的MC1568的全身给药和TSA对Rm的作用，表明PPN钙介导的伽马能带振荡随时间逐渐恢复功能。另外，在较低剂量（4 mg / kg）下，MC1568和TSA引起较高的平均振幅伽马振荡。阻断HDAC I类可能不会对伽马活性产生有害影响，但更重要的是，抑制HDAC I类（在100 mg / kg时）会增加伽马能带振荡。总之，目前的体内研究结果验证了我们先前在体外的发现，并进一步扩大了HDAC抑制对PPN节律的影响的信息。