Activation of AMPA Receptors in the Suprachiasmatic Nucleus Phase-Shifts the Mouse Circadian Clock In Vivo and In Vitro

Mizoro, Yasutaka; Yamaguchi, Yoshiaki; Kitazawa, Rena; Yamada, Hiroyuki; Matsuo, Masahiro; Fustin, Jean‐Michel; Doi, Masao; Okamura, Hitoshi

doi:10.1371/journal.pone.0010951

Cited by 30 publications

(27 citation statements)

References 34 publications

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“…S10 A and B, white boxes). GluR4 is expressed in the SCN; however, not all SCN neurons express GluR4 (28). Therefore, some of the tdTomato and Vglut2 double-positive puncta did not show apposition with GluR4.…”

Section: Retinal Projections To the Scn: Identification Of Postsynaptmentioning

confidence: 93%

Architecture of retinal projections to the central circadian pacemaker

Fernandez

Chang

Hattar

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

137

134

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The suprachiasmatic nucleus (SCN) receives direct retinal input from the intrinsically photosensitive retinal ganglion cells (ipRGCs) for circadian photoentrainment. Interestingly, the SCN is the only brain region that receives equal inputs from the left and right eyes. Despite morphological assessments showing that axonal fibers originating from ipRGCs cover the entire SCN, physiological evidence suggests that only vasoactive intestinal polypeptide (VIP)/ gastrin-releasing peptide (GRP) cells located ventrally in the SCN receive retinal input. It is still unclear, therefore, which subpopulation of SCN neurons receives synaptic input from the retina and how the SCN receives equal inputs from both eyes. Here, using single ipRGC axonal tracing and a confocal microscopic analysis in mice, we show that ipRGCs have elaborate innervation patterns throughout the entire SCN. Unlike conventional retinal ganglion cells (RGCs) that innervate visual targets either ipsilaterally or contralaterally, a single ipRGC can bilaterally innervate the SCN. ipRGCs form synaptic contacts with major peptidergic cells of the SCN, including VIP, GRP, and arginine vasopressin (AVP) neurons, with each ipRGC innervating specific subdomains of the SCN. Furthermore, a single SCNprojecting ipRGC can send collateral inputs to many other brain regions. However, the size and complexity of the axonal arborizations in non-SCN regions are less elaborate than those in the SCN. Our results provide a better understanding of how retinal neurons connect to the central circadian pacemaker to synchronize endogenous circadian clocks with the solar day.melanopsin | circadian | suprachiasmatic nucleus | non-image-forming functions | ipRGCs T he suprachiasmatic nucleus (SCN) houses a central pacemaker that orchestrates circadian (circa: "about" and diem: "day") behaviors that cycle with a period close to 24 h. This endogenous clock is self-sustained even in the complete absence of external stimuli, but can be entrained to the light/dark cycle of the solar day in a process defined as circadian photoentrainment (1). In mammals, phototransduction solely occurs in the retina (2). Retinal ganglion cells (RGCs) are projection neurons of the retina that send light information to brain targets (3). Although the majority of RGCs project to brain areas involved in object tracking and image formation, some RGCs also innervate non-image-forming brain regions to influence circadian activity, sleep, the pupillary light response, mood, and learning functions (4).Recent studies showed that a small subpopulation of RGCs expresses a photopigment called melanopsin (Opn4), making these cells intrinsically photosensitive (ip)RGCs (5-7). It is now known that there are at least five different ipRGC subtypes (M1-M5) (8, 9). Using genetic tracing techniques, it was shown that ipRGCs send projections to non-image-forming centers in the brain, including the SCN, which receives retinal input predominantly from M1 ipRGCs (10-12) and to a lesser extent from M2 ipRGCs (12). The SCN is a smal...

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Section: Retinal Projections To the Scn: Identification Of Postsynaptmentioning

confidence: 93%

Architecture of retinal projections to the central circadian pacemaker

Fernandez

Chang

Hattar

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

137

134

View full text Add to dashboard Cite

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“…AMPA receptors are thought to be critical for entrainment by relaying photic information to the SCN. 101 …”

Section: Rapid-acting Antidepressant Treatmentsmentioning

confidence: 99%

“…103 It is hypothesized that both AMPA and N -methyl-D-aspartate (NMDA) signaling reciprocally regulate glutamatergic signaling and the magnitude of phase-shifts. 101 …”

Section: Rapid-acting Antidepressant Treatmentsmentioning

confidence: 99%

Circadian dysregulation of clock genes: clues to rapid treatments in major depressive disorder

et al. 2014

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Conventional antidepressants require 2–8 weeks for a full clinical response. In contrast, two rapidly acting antidepressant interventions, low-dose ketamine and sleep deprivation (SD) therapy, act within hours to robustly decrease depressive symptoms in a subgroup of major depressive disorder (MDD) patients. Evidence that MDD may be a circadian-related illness is based, in part, on a large set of clinical data showing that diurnal rhythmicity (sleep, temperature, mood and hormone secretion) is altered during depressive episodes. In a microarray study, we observed widespread changes in cyclic gene expression in six regions of postmortem brain tissue of depressed patients matched with controls for time-of-death (TOD). We screened 12 000 transcripts and observed that the core clock genes, essential for controlling virtually all rhythms in the body, showed robust 24-h sinusoidal expression patterns in six brain regions in control subjects. In MDD patients matched for TOD with controls, the expression patterns of the clock genes in brain were significantly dysregulated. Some of the most robust changes were seen in anterior cingulate (ACC). These findings suggest that in addition to structural abnormalities, lesion studies, and the large body of functional brain imaging studies reporting increased activation in the ACC of depressed patients who respond to a wide range of therapies, there may be a circadian dysregulation in clock gene expression in a subgroup of MDDs. Here, we review human, animal and neuronal cell culture data suggesting that both low-dose ketamine and SD can modulate circadian rhythms. We hypothesize that the rapid antidepressant actions of ketamine and SD may act, in part, to reset abnormal clock genes in MDD to restore and stabilize circadian rhythmicity. Conversely, clinical relapse may reflect a desynchronization of the clock, indicative of a reactivation of abnormal clock gene function. Future work could involve identifying specific small molecules capable of resetting and stabilizing clock genes to evaluate if they can rapidly relieve symptoms and sustain improvement.

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“…), which are expressed in the retino‐recipient area of the SCN (Mizoro et al . ). Moreover, AMPA application similar to glutamate application into the SCN mimics light‐induced phase shifts in behavior (Gompf et al .…”

Section: Discussionmentioning

confidence: 97%

“…; Mizoro et al . ) and the light induction of c‐fos and Per gene expression within SCN cells (Golombek & Rosenstein ; Moriya et al . ).…”

Section: Discussionmentioning

confidence: 99%

The cell adhesion molecule EphA4 is involved in circadian clock functions

Kiessling

O’Callaghan

Freyburger

et al. 2017

Genes Brain and Behavior

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Circadian (∼24 h) rhythms of cellular network plasticity in the central circadian clock, the suprachiasmatic nucleus (SCN), have been described. The neuronal network in the SCN regulates photic resetting of the circadian clock as well as stability of the circadian system during both entrained and constant conditions. EphA4, a cell adhesion molecule regulating synaptic plasticity by controlling connections of neurons and astrocytes, is expressed in the SCN. To address whether EphA4 plays a role in circadian photoreception and influences the neuronal network of the SCN, we have analyzed circadian wheel-running behavior of EphA4 knockout (EphA4 ) mice under different light conditions and upon photic resetting, as well as their light-induced protein response in the SCN. EphA4 mice exhibited reduced wheel-running activity, longer endogenous periods under constant darkness and shorter periods under constant light conditions, suggesting an effect of EphA4 on SCN function. Moreover, EphA4 mice exhibited suppressed phase delays of their wheel-running activity following a light pulse during the beginning of the subjective night (CT15). Accordingly, light-induced c-FOS (FBJ murine osteosarcoma viral oncogene homolog) expression was diminished. Our results suggest a circadian role for EphA4 in the SCN neuronal network, affecting the circadian system and contributing to the circadian response to light.

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Activation of AMPA Receptors in the Suprachiasmatic Nucleus Phase-Shifts the Mouse Circadian Clock In Vivo and In Vitro

Cited by 30 publications

References 34 publications

Architecture of retinal projections to the central circadian pacemaker

Architecture of retinal projections to the central circadian pacemaker

Circadian dysregulation of clock genes: clues to rapid treatments in major depressive disorder

The cell adhesion molecule EphA4 is involved in circadian clock functions

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