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

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.

Bottom‐up gamma and bipolar disorder, clinical and neuroepigenetic implications

“…The fact that the PPN modulates both waking and REM sleep, the two states with prominent EEG gamma band activity, suggests that TSA blockade of intrinsic membrane gamma oscillations eliminates a major process subserved by gamma band frequency activity, arousal. Our discovery suggests that this constant flow of continuous sensory information through the induction of gamma oscillations may be modulating the transcription of genes in PPN neurons . This represents a potential neuroepigenetic mechanism not previously considered, but which carries significant implications.…”

“…Our results showed that, (a) acute in vitro exposure to the histone acetylation inhibitor trichostatin A (TSA) led to the elimination of high threshold, voltage-dependent Ca 2+ channel-mediated intrinsic membrane oscillations, specifically in the gamma band range but not lower frequencies, (b) pre-incubation with TSA led to a similar decrease specifically in gamma band oscillations, (c) a significant reduction in Ca 2+ currents was elicited by the same histone acetylation inhibitor, d) a HDAC Class I inhibitor, MS275, failed to affect intrinsic gamma oscillations in PPN neurons, and e) a HDAC Class IIb inhibitor, MC1568, blocked gamma oscillations. 88 These results suggest that there is a specific effect on gamma band oscillations when histone deacetylation via HDACIIb is blocked, suggesting that gamma oscillations related to arousal could be modulated by the balance between histone acetylation and deacetylation.…”

“…Figure is a diagram of the relationship between P/Q‐type Ca 2+ channels, CaMKII, and the interaction with HDAC Class IIs. Table summarizes the effects of the agents used in this study …”

“…Deacetylation of histones facilitates transcription. MC 1568, a HDAC Class II b inhibitor blocked oscillations, while MS 275, a HDAC Class I inhibitor did not affect oscillations . The minus (‐) signs denote inhibition by TSA of HDAC class I and HDAC class II ; inhibition of HDAC class I by MS 275' and inhibition of HDAC class II by MC 1568 [Colour figure can be viewed at wileyonlinelibrary.com]…”

“…MC1568, a HDAC Class IIb inhibitor blocked oscillations, while MS275, a HDAC Class I inhibitor did not affect oscillations. 88 The minus (-) signs denote inhibition by TSA of HDAC class I and HDAC class II; inhibition of HDAC class I by MS275' and inhibition of HDAC class II by MC1568 [Colour figure can be viewed at wileyonlinelibrary.com] membrane gamma oscillations eliminates a major process subserved by gamma band frequency activity, arousal. Our discovery suggests that this constant flow of continuous sensory information through the induction of gamma oscillations may be modulating the transcription of genes in PPN neurons.…”