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 .

Proteomic measures of gamma oscillations

“…Furthermore, TSA's rapid effects in vitro might be due to the acetylation of multiple proteins located outside the nucleus (Choudhary et al., 2009). Indeed, we have suggested that alterations in the acetylation/deacetylation equilibrium may blunt the Ca 2+ -CAM kinase II homeostatic modulation of P/Q-type calcium channels (Urbano et al., 2018; Garcia-Rill et al., 2019). The stock solution of TSA was dissolved in DMSO and immediately stored at -30 °C.…”

Gamma oscillations in the pedunculopontine nucleus are regulated by F-actin: neuroepigenetic implications

“…The pedunculopontine nucleus (PPN) is most active during the two states of arousal, waking, and rapid eye movement sleep (10,19). The PPN modulates ascending projections through the thalamus influencing arousal and descending projections through the pons and medulla modulating posture and locomotion (11,19). PPN neuronal activity in the beta/gammafrequency range has been confirmed in vivo in the cortical EEG and PPN of the cat when the animal is active (33) and in the region of the PPN in humans during stepping but not at rest (12).…”

“…Recent discoveries have determined the mechanisms behind gamma-band activity in the PPN to be mediated by voltagedependent, high-threshold N-and P/Q-type Ca 2ϩ channels that are expressed in every PPN neuron (10,11,14,15,19,20,35). These Ca 2ϩ channel subtypes are modulated by different intracellular pathways: N-type by the cAMP/PK pathway and P/Q-type via the calcium calmodulin kinase II (CaMKII) pathway (9,23,24).…”

“…Epigenetic mechanisms (i.e., histone posttranslational modification and DNA methylation) play a role in regulation of gene expression in response to a wide range of environmental stimuli, such as learning, stress, or drugs of abuse (4). The recent results of our group showed that 1) acute in vitro exposure to the histone deacetylation inhibitor trichostatin A (TSA) led to lower activation of high threshold, voltage-dependent Ca 2ϩ channel-mediated intrinsic membrane oscillations, specifically in the gamma-band range, but not lower frequency oscillations; 2) preincubation with TSA led to a similar decrease specifically in gamma-band oscillations; and 3) a significant reduction in calcium currents was elicited by TSA (11,34). These changes in PPN rhythmicity could be explained by decreased deacetylation of histones (i.e., changes in gene expression) and/or changes in the deacetylation of other protein targets like CaMKII and F-actin (2,5).…”

Investigação da associação de variantes polimórficas, sítios de metilação e tamanho de telômeros com resposta a longo prazo de lítio em transtorno bipolar

“…). Alguns estudos mostraram associação entre maior expressão tecidual dessa proteína em cérebros de portadores de TB(Garcia-Rill et al, 2019). Lítio inibe a interação entre NCS-1 e IP3R em neurônios do núcleo pedunculopontino, que participa do sistema ativador reticular regulando oscilações corticais de alta frequência tipo gama(D´Onofrio et al, 2017).…”