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

Abstract

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 (InsP ₃R). NCS‐1 is known to enhance the activity of InsP ₃R, and of Ca ²⁺‐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 Ca ²⁺ channel activity, whereas NCS‐1 reduced the effect of Li ⁺ on Ca ²⁺ currents. These effects were mediated by a G‐protein overinhibition of Ca ²⁺ currents. These results suggest that Li ⁺ affected intracellular pathways involving the activation of voltage‐gated Ca ²⁺ 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.