Cyclin-dependent kinase 5 (Cdk5) activity is modulated by light and gates rapid phase shifts of the circadian clock

  1. Andrea Brenna
  2. Micaela Borsa
  3. Gabriella Saro
  4. Jürgen A. Ripperger
  5. Dominique A. Glauser
  6. Zhihong Yang
  7. Antoine Adamantidis
  8. Urs Albrecht

  • Curated by eLife

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    eLife assessment

    This important chronobiological study in mice suggests that light modulated activity of Cdk5 activity on the PKA-CaMK-CREB signaling pathway provides missing molecular mechanistic details to understand light- induced circadian clock phase delays during the early night, but not for phase advances in the morning. The authors provide overall convincing evidence bridging from behavioral to molecular/cellular experiments to neural activity imaging.

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Abstract

The circadian clock enables organisms to synchronize biochemical and physiological processes over a 24-hour period. Natural changes in lighting conditions, as well as artificial disruptions like jet lag or shift work, can advance or delay the clock phase to align physiology with the environment. Within the suprachiasmatic nucleus (SCN) of the hypothalamus, circadian timekeeping and resetting rely on both membrane depolarization and intracellular second-messenger signaling. Voltage-gated calcium channels (VGCCs) facilitate calcium influx in both processes, activating intracellular signaling pathways that trigger Period ( Per ) gene expression. However, the precise mechanism by which these processes are concertedly gated remains unknown.

Our study demonstrates that cyclin-dependent kinase 5 (Cdk5) activity is modulated by light and regulates phase shifts of the circadian clock. We observed that knocking down Cdk5 in the SCN of mice affects phase delays but not phase advances. This is linked to uncontrolled calcium influx into SCN neurons and an unregulated protein kinase A (PKA) – calcium/calmodulin-dependent kinase (CaMK) – cAMP response element-binding protein (CREB) signaling pathway. Consequently, genes such as Per1 are not induced by light in the SCN of Cdk5 knock-down mice. Our experiments identified Cdk5 as a crucial light-modulated kinase that influences rapid clock phase adaptation. This finding elucidates how light responsiveness and clock phase coordination adapt activity onset to seasonal changes, jet lag, and shift work.

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  1. Version published to 10.1101/2024.02.08.579499v2 on bioRxiv
  2. Version published to 10.7554/elife.97029 on eLife
  3. Version published to 10.7554/elife.97029.1 on eLife
  4. eLife

    eLife assessment

    This important chronobiological study in mice suggests that light modulated activity of Cdk5 activity on the PKA-CaMK-CREB signaling pathway provides missing molecular mechanistic details to understand light- induced circadian clock phase delays during the early night, but not for phase advances in the morning. The authors provide overall convincing evidence bridging from behavioral to molecular/cellular experiments to neural activity imaging.

  5. eLife

    Reviewer #1 (Public Review):

    In the manuscript "Cyclin-dependent kinase 5 (Cdk5) activity is modulated by light and gates rapid phase shifts of the circadian clock", Brenna et al study the role of Cdk5 on circadian rhythms and they conclude that the CDK5 gates the activity of light on phase shifts at ZT by showing that the behavioural shifts to light as a result of CDK5 silencing only affect light-induced phase shifts at ZT/CT 14 but not at other times.

    Further, they delineate the mechanism behind this phenotype and demonstrate that 1) CDK5 activity is downregulated following a light pulse via a loss of interaction with p35 and demonstrate this via an activity assay. 2) knock-down of CDK5: increases CREB, CAMK-ii/iv phosphorylation, likely via increasing calcium levels along with alterations to the localisation of Cav3.1, 3) reduces: light-induced response in vivo at ZT14 in the SCN.

    They suggest this mechanism involves light 'silencing' CDK5-pathway (possibly by disrupting P35 interaction and dysregulating this pathway) which under basal conditions phosphorylates DARP32 leading to PKA inhibition and by extension reduction in activation of the calcium-calmodulin kinase activity and leading to reduced CREB activity. The authors finally evaluate gene expression changes of previously described light-responsive-genes in at ZT14 and the SCN.

    This is an interesting piece of work that explains how circadian responses to light could be gated and is generally well supported by a wealth of data. Whilst I found the overall involvement of CDK5 in gating light response interesting and convincing, I have some concerns about their interpretation of the data surrounding the mechanism, which I have detailed below. I also think this manuscript could be improved with a slightly different structure and concise discussion for the benefit of a broader scientific audience.

  6. eLife

    Reviewer #2 (Public Review):

    Summary:

    Definition of the role of CdK5 in circadian locator activity and light induced neural activity in the mouse SCN in-vivo revealing its mode of action through PKA-CaMK-CREB signaling pathway.

    Strengths:

    The experimental approaches are carried from in-vivo, to cellular and molecular level and provide first evidence for the specific involvement of CdK5 in light-induced phase advance of the free-running rhythm.

    Weaknesses:

    The behavioral analyses are limited to some selected parameters.
    Downstream effects on circadian oscillation of gene expression and physiological functions in other brain regions, and organs is missing.

  7. Version published to 10.1101/2024.02.08.579499v1 on bioRxiv