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

Abstract

Objectives: This limited review examines the role of the reticular activating system (RAS), especially the pedunculopontine nucleus (PPN), one site of origin of bottom-up gamma, in the symptoms of bipolar disorder (BD).

Methods: The expression of neuronal calcium sensor protein 1 (NCS-1) in the brains of BD patients is increased. It has recently been found that all PPN neurons manifest intrinsic membrane beta/gamma frequency oscillations mediated by high threshold calcium channels, suggesting that it is one source of bottom-up gamma. This review specifically addresses the involvement of these channels in the manifestation of BD.

Results: Excess NCS-1 was found to dampen gamma band oscillations in PPN neurons. Lithium, a first line treatment for BD, was found to decrease the effects of NCS-1 on gamma band oscillations in PPN neurons. Moreover, gamma band oscillations appear to epigenetically modulate gene transcription in PPN neurons, providing a new direction for research in BD.

Conclusions: This is an area needing much additional research, especially since the dysregulation of calcium channels may help explain many of the disorders of arousal in, elicit unwanted neuroepigenetic modulation in, and point to novel therapeutic avenues for, BD.

Keywords: Arousal; Ca2+ channels; NCS-1; REM sleep; binding; gamma oscillations; lithium; neuroepigenetics; preconscious awareness; waking.

Figure 1

Waking vs REM sleep gamma mechanisms. The Cortical EEG looks the same during waking and REM sleep, but it is coherent across regions during waking and non‐coherent during REM sleep. The cortical EEG, therefore, is driven by the RAS, which regulates waking and sleep. Cells in the PPN modulate gamma oscillations during waking through P/Q‐type calcium channels that are under the control of CaMKII, while cells in the PPN that modulate REM sleep do so through N‐type calcium channels that are under the control of cAMP/PKA. In BD, NCS‐1 is over expressed (note double arrows to denote over expression) and its excess decreases CaMKII and P/Q‐type driven gamma oscillations to decrease the maintenance of gamma band activity during waking. This may also lead to excessive REM sleep drive. Li⁺ inhibits the action of over expressed NCS‐1 in order to restore the generation of gamma band oscillations during waking [Colour figure can be viewed at wileyonlinelibrary.com]

Figure 2

P/Q‐type channels, CaMKII, and HDAC Class II interactions. During waking, gamma oscillations mediated by P/Q‐type Ca²⁺ channels lead to Ca²⁺ entry and interaction with CaMKII. In turn, CaMKII leads to phosphorylation of HDAC Class IIs that have left the nucleus (while HDAC Class Is remain in the nucleus). The complex between CaMKII and HDAC Class IIs is maintained by Ca²⁺ entry, in the case of P/Q‐type channels, specifically during waking. Deacetylation of histones facilitates transcription. 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]

Figure 3

Bottom‐up gamma in bipolar disorder. Afferent input helps activate PPN neurons that manifest intrinsic gamma band oscillations through high threshold, voltage‐dependent calcium channels. These cells project to the intralaminar thalamus (ILT)89, 90 that also manifests these calcium channels to drive cortical activity by terminating in layers I and II. When NCS‐1 is over expressed (NCS‐1 with multiple ++), these oscillations are reduced, but Li⁺ therapy (Li⁺ + NCS‐1) will restore intrinsic gamma band oscillations, perhaps both in the PPN (left side, red records) and ILT (right side, blue records), among other regions. We assume that too much Li⁺ will over inhibit NCS‐1 and decrease oscillations, while too little Li⁺ will not overcome the suppression of oscillations by over expressed NCS‐1. This suggests, in keeping with standard therapy, that concentrations of Li⁺ should be maintained at an optimal level [Colour figure can be viewed at wileyonlinelibrary.com]