Activation of mGluR1 negatively modulates glutamate-induced phase shifts of the circadian pacemaker in the mouse suprachiasmatic nucleus

Yoon Sik Kim; C Justin Lee; Ji-Hyeon Kim; Young-Beom Kim; Christopher S Colwell; Yang In Kim

doi:10.1016/j.nbscr.2023.100089

Activation of mGluR1 negatively modulates glutamate-induced phase shifts of the circadian pacemaker in the mouse suprachiasmatic nucleus

Neurobiol Sleep Circadian Rhythms. 2023 Feb 19:14:100089. doi: 10.1016/j.nbscr.2023.100089. eCollection 2023 May.

Authors

Yoon Sik Kim¹, C Justin Lee², Ji-Hyeon Kim¹, Young-Beom Kim¹, Christopher S Colwell³, Yang In Kim¹

Affiliations

¹ Department of Physiology and Neuroscience Research Institute, Korea University College of Medicine, Seoul, 136-705, Republic of Korea.
² Center for Cognition and Sociality, Institute for Basic Science (IBS), Daejeon, Republic of Korea.
³ Department of Psychiatry & Biobehavioral Sciences, University of California-Los Angeles, 760 Westwood Plaza, Los Angeles, CA, 90024, USA.

Abstract

In mammals, photic information delivered to the suprachiasmatic nucleus (SCN) via the retinohypothalamic tract (RHT) plays a crucial role in synchronizing the master circadian clock located in the SCN to the solar cycle. It is well known that glutamate released from the RHT terminals initiates the synchronizing process by activating ionotropic glutamate receptors (iGluRs) on retinorecipient SCN neurons. The potential role of metabotropic glutamate receptors (mGluRs) in modulating this signaling pathway has received less attention. In this study, using extracellular single-unit recordings in mouse SCN slices, we investigated the possible roles of the G_q/11 protein-coupled mGluRs, mGluR1 and mGluR5, in photic resetting. We found that mGluR1 activation in the early night produced phase advances in neural activity rhythms in the SCN, while activation in the late night produced phase delays. In contrast, mGluR5 activation had no significant effect on the phase of these rhythms. Interestingly, mGluR1 activation antagonized phase shifts induced by glutamate through a mechanism that was dependent upon Ca_V1.3 L-type voltage-gated Ca²⁺ channels (VGCCs). While both mGluR1-evoked phase delays and advances were inhibited by knockout (KO) of Ca_V1.3 L-type VGCCs, different signaling pathways appeared to be involved in mediating these effects, with mGluR1 working via protein kinase G in the early night and via protein kinase A signaling in the late night. We conclude that, in the mouse SCN, mGluR1s function to negatively modulate glutamate-evoked phase shifts.

Keywords: CaV1.3; Glutamate; PKA; PKG; Suprachiasmatic nucleus; mGluR.