Lithium decreases the effects of neuronal calcium sensor protein 1 in pedunculopontine neurons

Human postmortem studies reported 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. Bipolar disorder is characterized by sleep dysregulation, suggesting a role for the reticular activating system (RAS). Lithium (Li+) has been shown to effectively treat the mood disturbances in bipolar disorder patients and was proposed to act by inhibiting the interaction between NCS-1 and inositol 1,4,5-triphosphate receptor protein (InsP3R). NCS-1 is known to enhance the activity of InsP3R, and of Ca2+-mediated gamma oscillatory activity in the pedunculopontine nucleus (PPN), part of the RAS. This study aimed to determine the nature of some of the intracellular mechanisms of Li+ on rat PPN cells and to identify the interaction between Li+ and NCS-1. Since Li+ has been shown to act by inhibiting the enhancing effects of NCS-1, we tested the hypothesis that Li+ would reduced the effects of overexpression of NCS-1 and prevent the downregulation of gamma band activity. Li+ decreased gamma oscillation frequency and amplitude by downregulating Ca2+ channel activity, whereas NCS-1 reduced the effect of Li+ on Ca2+ currents. These effects were mediated by a G-protein overinhibition of Ca2+ currents. These results suggest that Li+ affected intracellular pathways involving the activation of voltage-gated Ca2+ channels mediated by an intracellular mechanism involving voltage-dependent activation of G proteins, thereby normalizing gamma band oscillations mediated by P/Q-type calcium channels modulated by NCS-1.