Modulation of gamma oscillations in the pedunculopontine nucleus by neuronal calcium sensor protein-1: relevance to schizophrenia and bipolar disorder

D’Onofrio, Stasia; Kezunovic, Nebojsa; Hyde, James; Luster, Brennon; Messias, Erick; Urbano, Francisco J.; García‐Rill, Edgar

doi:10.1152/jn.00828.2014

Cited by 31 publications

(53 citation statements)

References 58 publications

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“…Our findings demonstrated that intracellular NCS-1 can exert a concentration-dependent biphasic effect on gamma band oscillatory activity of PPN neurons [123]. That is, low concentrations promoted, while high concentrations of NCS-1 blocked, gamma band oscillations.…”

Section: Introductionmentioning

confidence: 61%

Role of Calcium Channels in Bipolar Disorder

D’Onofrio

Mahaffey

García‐Rill

2018

CPSP

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Bipolar disorder is characterized by a host of sleep-wake abnormalities that suggests that the reticular activating system (RAS) is involved in these symptoms. One of the signs of the disease is a decrease in high frequency gamma band activity, which accounts for a number of additional deficits. Bipolar disorder has also been found to overexpress neuronal calcium sensor protein 1 (NCS-1). Recent studies showed that elements in the RAS generate gamma band activity that is mediated by high threshold calcium (Ca2+) channels. This mini-review provides a description of recent findings on the role of Ca2+ and Ca2+ channels in bipolar disorder, emphasizing the involvement of arousal-related systems in the manifestation of many of the disease symptoms. This will hopefully bring attention to a much-needed area of research and provide novel avenues for therapeutic development.

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Section: Introductionmentioning

confidence: 61%

Role of Calcium Channels in Bipolar Disorder

D’Onofrio

Mahaffey

García‐Rill

2018

CPSP

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“…We discovered that intracellular NCS‐1 had a concentration‐dependent effect on beta/gamma oscillatory activity in PPN neurons . While lower levels of NCS‐1 enhanced oscillation amplitude at long latency, higher levels of NCS‐1 had an early enhancing effect of oscillation amplitude that was followed by an inhibitory effect, ultimately reducing the amplitude of gamma oscillations.…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2018

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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 .

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“…That is, the effects of over expression of NCS-1 in bipolar disorder may be decreased by lithium. As shown above, excessive NCS-1 decreased gamma oscillations (D’Onofrio et al 2015a), therefore, lithium may prevent the down regulation of gamma band activity and restore normal levels of gamma band oscillations. These findings taken together resolve a 60 year mystery of how lithium works in bipolar disorder.…”

Section: Implications For Schizophrenia and Bipolar Disordermentioning

confidence: 92%

“…We recorded PPN neurons in the presence of fast synaptic blockers and terodotoxin with various concentrations of NCS-1 in the recording pipette using whole cell patch clamp (D’Onofrio et al 2015a). Figure 4A shows that very low concentrations of NCS-1 (0.5 µM) had minor effects, while higher concentrations (1 µM) increased the amplitude of ramp-induced oscillations (not shown), and very high concentrations of NCS-1 (10 µM) blocked the beta/gamma oscillations (Figure 4B).…”

Section: Implications For Schizophrenia and Bipolar Disordermentioning

confidence: 99%

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Implications of gamma band activity in the pedunculopontine nucleus

et al. 2015

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The fact that the pedunculopontine nucleus (PPN) is part of the reticular activating system places it in a unique position to modulate sensory input and fight-or-flight responses. Arousing stimuli simultaneously activate ascending projections of the PPN to the intralaminar thalamus to trigger cortical high frequency activity and arousal, as well as descending projections to reticulospinal systems to alter posture and locomotion. As such, the PPN has become a target for deep brain stimulation (DBS) for the treatment of Parkinson’s disease (PD), modulating gait, posture, and higher functions. This article describes the latest discoveries on PPN physiology and the role of the PPN in a number of disorders. It has now been determined that high frequency activity during waking and REM sleep is controlled by two different intracellular pathways and two calcium channels in PPN cells. Moreover, there are three different PPN cell types that have one or both calcium channels and may be active during waking only, REM sleep only, or both. Based on the new discoveries, novel mechanisms are proposed for insomnia as a waking disorder. In addition, neuronal calcium sensor protein-1 (NCS-1), which is over expressed in schizophrenia and bipolar disorder, may be responsible for the dysregulation in gamma band activity in at least some patients with these diseases. Recent results suggest that NCS-1 modulates PPN gamma band activity and that lithium acts to reduce the effects of over expressed NCS-1, accounting for its effectiveness in bipolar disorder.

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Modulation of gamma oscillations in the pedunculopontine nucleus by neuronal calcium sensor protein-1: relevance to schizophrenia and bipolar disorder

Cited by 31 publications

References 58 publications

Role of Calcium Channels in Bipolar Disorder

Role of Calcium Channels in Bipolar Disorder

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

Implications of gamma band activity in the pedunculopontine nucleus

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