Activation of NMDA Receptors in the Suprachiasmatic Nucleus Produces Light-Like Phase Shifts of the Circadian ClockIn Vivo

Abstract

Although there is substantial evidence that glutamate mimics the effects of light on the mammalian circadian clock in vitro, it has been reported that microinjection of glutamate into the suprachiasmatic nucleus of the hypothalamus (SCN) region in vivo does not result in a pattern of phase shifts that mimic those caused by light pulses. The present study was designed to test the hypothesis that microinjection of NMDA into the SCN would induce light-like phase shifts of the circadian clock through activation of the NMDA receptor. Hamsters housed in constant darkness received microinjections of NMDA through guide cannulas aimed at the SCN region at various times throughout the circadian cycle. Wheel running was monitored as a measure of circadian phase. Microinjection of NMDA resulted in circadian phase shifts, the size and direction of which were dependent on the time of injection. The resulting phase-response curve closely resembled that of light. The circadian response showed a clear dose-dependence at circadian time (CT) 13.5 but not at CT19. Both phase delays and advances induced by NMDA were blocked by coinjection of the NMDA antagonist 2-amino-5-phosphopentanoic acid but were slightly attenuated by the non-NMDA antagonist 6-nitro-7-sulfamoylbenzo[f]quinoxaline-2,3-dione disodium. The ability of NMDA to induce phase shifts was not altered by coinjection with tetrodotoxin. These data are consistent with the hypothesis that activation of NMDA receptors is a critical step in the transmission of photic information to the SCN.

Deficiency of tumor suppressor NDRG2 leads to attention deficit and hyperactive behavior

“…Two-month-old Ndrg2 -/-mice exhibited significantly increased locomotor activity in their individual home cages compared with their WT littermates over the course of 24 hours (Supplemental Figure 3). Ndrg2 -/-mice had much higher locomotor activity at night than during the day, which is consistent with their nocturnal nature (23,24). We then examined mouse locomotor activities with the open-field test and found that the Ndrg2 -/-mice showed a significant increase in total distance traveled (approximately 2-fold) and number of lines crossed ( Figure 1, A and B).…”

Effect of Haloperidol on mPer1 Gene Expression in Mouse Suprachiasmatic Nuclei

“…NMDA receptor antagonist MK-801 suppresses the photic resetting of behavioral rhythms (49) and also reduces the c-fos, Per1, and Per2 mRNA induction by light in the SCN (50,51). In addition, NMDA application to the SCN elicits a phase shift in wheelrunning rhythm (52). Hal also affects the serotonin receptors (28,30,31).…”

Acute ethanol modulates glutamatergic and serotonergic phase shifts of the mouse circadian clock in vitro

“…This signaling primarily involves glutamate acting on SCN NMDA and AMPA receptors. Light (in vivo) and glutamate (in vitro) presented during the night robustly phase-shift the SCN clock; these effects are mimicked by NMDA (Ding et al, 1994;Mintz et al, 1999;Mintz and Albers, 1997;Gamble et al, 2004) and blocked by NMDA antagonists (Abe et al, 1992;Rea et al, 1993). NMDA receptors are one of the principal targets of ethanol in the brain (Lovinger et al, 1989;Abrous et al, 2005;Krystal et al, 2003;Chandler, 2003).…”

“…Given the strong inhibitory effect of acute ethanol on glutamatergic signaling (Ron, 2004;Chandler, 2003;Woodward, 2000;Krystal et al, 2003) including in the SCN (Ruby et al, 2006; data presented here), we hypothesize that ethanol enhances serotonergic phase shifts through inhibiting glutamate signaling. To test this, we co-applied DPAT with a variety of agents that inhibit photic/glutamate signaling in the SCN, including AP5, NBQX, K252a and L-NAME Ding et al, 1994;Mintz et al, 1999;Schurov et al, 1999;Michel et al, 2006;Kallingal and Mintz, 2006). In each case, the antagonist treatment enhanced DPATinduced phase advances by about 50%.…”