Class II histone deacetylases require P/Q-type Ca2+ channels and CaMKII to maintain gamma oscillations in the pedunculopontine nucleus

Sci Rep. 2018 Sep 3;8(1):13156. doi: 10.1038/s41598-018-31584-2.

Abstract

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 Ca2+ 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) Ca2+ currents (ICa) 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Benzamides / pharmacology
  • Benzylamines / pharmacology
  • Calcium Channels, P-Type / genetics*
  • Calcium Channels, P-Type / metabolism
  • Calcium Channels, Q-Type / genetics*
  • Calcium Channels, Q-Type / metabolism
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / genetics*
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism
  • Gamma Rhythm / drug effects
  • Gamma Rhythm / physiology
  • Gene Expression Regulation
  • Histone Deacetylase Inhibitors / pharmacology*
  • Histone Deacetylases / genetics*
  • Histone Deacetylases / metabolism
  • Hydroxamic Acids / pharmacology
  • Indoles / pharmacology
  • Microtomy
  • Neurons / cytology
  • Neurons / drug effects*
  • Neurons / metabolism
  • Pedunculopontine Tegmental Nucleus / cytology
  • Pedunculopontine Tegmental Nucleus / drug effects*
  • Pedunculopontine Tegmental Nucleus / metabolism
  • Primary Cell Culture
  • Pyridines / pharmacology
  • Pyrroles / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction
  • Sulfonamides / pharmacology
  • Tissue Culture Techniques
  • Transcription, Genetic

Substances

  • Benzamides
  • Benzylamines
  • Calcium Channels, P-Type
  • Calcium Channels, Q-Type
  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • Indoles
  • MC1568
  • Pyridines
  • Pyrroles
  • Sulfonamides
  • KN 93
  • entinostat
  • tubastatin A
  • trichostatin A
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • Histone Deacetylases