Interaction between neuronal calcium sensor protein 1 and lithium in pedunculopontine neurons.

Stasia D'Onofrio,James Hyde,Edgar Garcia-Rill

doi:10.14814/phy2.13246

Abstract

Bipolar disorder is characterized by sleep dysregulation, suggesting a role for the reticular activating system (RAS). Postmortem studies showed increased expression of neuronal calcium sensor protein 1 (NCS‐1) in the brains of some bipolar disorder patients, and reduced or aberrant gamma band activity is present in the same disorder. Lithium (Li+) has been shown to effectively treat the mood disturbances in bipolar disorder patients. We previously showed that NCS‐1 at low levels increased, and at high levels decreased, gamma oscillations in RAS pedunculopontine neurons (PPN), and that Li+ decreased these oscillations. We previously described the effects of each agent on oscillations, G‐protein mechanisms, and Ca2+ currents. However, we designed the present experiments to determine the nature of the interaction of NCS‐1 and Li+ at physiological concentrations that would have an effect within minutes of application. As expected, Li+ decreased gamma oscillation amplitude, while NCS‐1 increased the amplitude of gamma oscillations. We identified NCS‐1 at 2 μmol/L as a concentration that increased gamma oscillations within 5–10 min, and Li+ at 10 μmol/L as a concentration that decreased gamma oscillations within 5 min. The combined application of NCS‐1 and Li+ at these concentrations showed that Li+ reduced the effects of NCS‐1 on oscillation amplitude within 5–10 min. These results demonstrate that at physiological levels, Li+ acts to reduce the effects of NCS‐1 so that, given over expression of NCS‐1, Li+ would have salutary effects.

Highlights

Human postmortem studies reported increased expression of high affinity, low capacity neuronal calcium sensor protein 1 (NCS-1) in the brains of some bipolar disorder and schizophrenic patients (Koh et al 2003)
Since our previous findings showed that pedunculopontine neurons (PPN) neurons cannot be effectively depolarized beyond À25 mV using square steps due to the activation of K+ channels during rapid depolarization (Kezunovic et al 2011, 2013), we studied the effects of NCS-1 and Li+ using a 1 sec depolarizing ramp, gradually changing the membrane potential from resting values up to 0 mV in current clamp mode, to induce membrane oscillations in all three groups of cells present in the PPN
We previously showed that low concentrations of NCS-1 increased the amplitude of gamma oscillations, but high concentrations reduced their amplitude (D’Onofrio et al 2015)

Summary

Introduction

Human postmortem studies reported increased expression of high affinity, low capacity neuronal calcium sensor protein 1 (NCS-1) in the brains of some bipolar disorder and schizophrenic patients (Koh et al 2003). Gamma band activity is disrupted in the same disorders that show over expression of NCS-1 (Senkowski and Gallinat 2015; Wynn et al 2015). Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.

Objectives

Methods

Results

Conclusion