Melatonin recovers sleep phase delayed by MK‐801 through the melatonin MT2 receptor‐ Ca2+‐CaMKII‐CREB pathway in the ventrolateral preoptic nucleus. Issue 3 (11th July 2020)

• Record Type: Journal Article
• Authors: Wang, Qian; Zhu, Dexiao; Ping, Shuo; Li, Chuangang; Pang, Kunkun; Zhu, Shaowei; Zhang, Jing; Comai, Stefano; Sun, Jinhao
• Is Part Of: Journal of pineal research. Volume 69:Issue 3(2020)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-07-11
• Subjects: calcium -- homeostatic mechanism -- melatonin -- MT2 receptors -- NMDA receptors -- sleep; Pineal gland -- Periodicals; Pineal Gland -- Periodicals; Épiphyse (Glande); Périodique électronique (Descripteur de forme); Ressource Internet (Descripteur de forme); 612.492
• DOI: 10.1111/jpi.12674
• Languages: English
• ISSNs: 0742-3098

Abstract

Abstract: Melatonin (MLT) is widely used to treat sleep disorders although the underlying mechanism is still elusive. In mice, using wheel‐running detection, we found that exogenous MLT could completely recover the period length prolonged by N‐methyl‐D‐aspartate receptor (NMDAR) impairment due to the injection of the NMDAR antagonist MK‐801, a preclinical model of psychosis. The analysis of the possible underlying mechanisms indicated that MLT could regulate the homeostatic state in the ventrolateral preoptic nucleus (VLPO) instead of the circadian process in the suprachiasmatic nucleus (SCN). In addition, our data showed that MK‐801 decreased Ca 2+ ‐related CaMKII expression and CREB phosphorylation levels in the VLPO, and MLT could rescue these intracellular impairments but not NMDAR expression levels. Accordingly, Gcamp6 AAV virus was injected in‐vivo to further monitor intracellular Ca 2+ levels in the VLPO, and MLT demonstrated a unique ability to increase Ca 2+ fluorescence compared with MK‐801‐injected mice. Additionally, using the selective melatonin MT2 receptor antagonist 4‐phenyl‐2‐propionamidotetralin (4P‐PDOT), we discovered that the pharmacological effects of MLT upon NMDAR impairments were mediated by melatonin MT2 receptors. Using electroencephalography/electromyography (EEG/EMG) recordings, we observed that the latency to the first nonrapid eye movement (NREM) sleep episode was delayed by MK‐801, and MLT was able to recover this delay. In conclusion, exogenous MLT by acting upon melatonin MT2 receptors rescues sleep phase delayed by NMDAR impairment via increasing intracellular Ca 2+ signaling in the VLPO, suggesting a regulatory role of the neurohormone on the homeostatic system.