Prefrontal cortex molecular clock modulates development of depression-like phenotype and rapid antidepressant response in mice.
David H. Sarrazin, Wilf Gardner, Carole Marchese, Martin Balzinger, Chockalingam Ramanathan, Marion Schott, Stanislav Rozov, Maxime Veleanu, Stefan Vestring, Claus Normann, Tomi Rantamäki, Benedicte Antoine, Michel Barrot, Etienne Challet, Patrice Bourgin, Tsvetan Serchov
Nature Communications August 23, 2024 DOI: 10.1038/s41467-024-51716-9 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Mouse model of depression |
| Interventions | Ketamine Per2 silencing REV-ERB agonism |
| Topics | Depression |
| Keywords | Chronobiology Mental health Depression treatment Brain research |
| Citations | 41 |
| Key findings | The mPFC molecular clock critically regulates depression-like behavior, and pharmacological clock manipulations can produce antidepressant-like effects through glutamatergic-dependent plasticity. |
Abstract
Depression is associated with dysregulated circadian rhythms, but the role of intrinsic clocks in mood-controlling brain regions remains poorly understood. We found increased circadian negative loop and decreased positive clock regulators expression in the medial prefrontal cortex (mPFC) of a mouse model of depression, and a subsequent clock countermodulation by the rapid antidepressant ketamine. Selective Bmal1KO in CaMK2a excitatory neurons revealed that the functional mPFC clock is an essential factor for the development of a depression-like phenotype and ketamine effects. Per2 silencing in mPFC produced antidepressant-like effects, while REV-ERB agonism enhanced the depression-like phenotype and suppressed ketamine action. Pharmacological potentiation of clock positive modulator ROR elicited antidepressant-like effects, upregulating plasticity protein Homer1a, synaptic AMPA receptors expression and plasticity-related slow wave activity specifically in the mPFC. Our data demonstrate a critical role for mPFC molecular clock in regulating depression-like behavior and the therapeutic potential of clock pharmacological manipulations influencing glutamatergic-dependent plasticity.
Comparable studies
Other preclinical and animal studies on depression, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psychedelics, but Not Ketamine, Produce Persistent Antidepressant-like Effects in a Rodent Experimental System for the Study of Depression Rats | 2020 | Preclinical study | |
| A Single Subanesthetic Dose of Ketamine Relieves Depression-like Behaviors Induced by Neuropathic Pain in Rats Rats with spared nerve injury (neuropathic pain model), sham-operated rats, and control... | 2011 | Animal experimental study | |
| Effects of N,N-Dimethyltryptamine on Rat Behaviors Relevant to Anxiety and Depression Adult male Sprague-Dawley rats | 2018 | Experimental study | |
| A non-hallucinogenic LSD analog with therapeutic potential for mood disorders. Mice and cultured rat cortical neurons | 2023 | Preclinical study | |
| Comparison of (R)-ketamine and lanicemine on depression-like phenotype and abnormal composition of gut microbiota in a social defeat stress model Susceptible mice after chronic social defeat stress | 2017 | Preclinical animal study |
Citations in the library
Cited by 7
- Lateral habenula astroglia modulate the potentiating antidepressant-like effects of bright light stimulation in intractable depression. Frontiers in Pharmacology 2025
- Effects of ketamine on sleep and circadian rhythmicity in major depressive disorder and bipolar disorder: A systematic review. Journal of Affective Disorders May 6, 2026
- Synaptic Plasticity-Intrinsic Excitability and Antidepressant Discovery. Biomedicines June 1, 2026
- A circuit dissection of perception-action decoupling in S-ketamine-induced hallucination-like states. Molecular Psychiatry September 19, 2026
- Effects of sub-anesthetic doses of esketamine on immune function and postoperative negative emotions in acoustic neuroma patients: a randomized clinical trial. Annals of medicine July 3, 2026
and 2 more in the library
Cites 7
- Ketamine-induced regulation of TrkB-GSK3β signaling is accompanied by slow EEG oscillations and sedation but is independent of hydroxynorketamine metabolites. Neuropharmacology October 1, 2019
- Cortical Excitability and Activation of TrkB Signaling During Rebound Slow Oscillations Are Critical for Rapid Antidepressant Responses. Molecular Neurobiology June 1, 2019
- Sustained rescue of prefrontal circuit dysfunction by antidepressant-induced spine formation Science April 12, 2019
- Increased Signaling via Adenosine A1 Receptors, Sleep Deprivation, Imipramine, and Ketamine Inhibit Depressive-like Behavior via Induction of Homer1a Neuron August 5, 2015
- NMDA Receptor Blockade at Rest Triggers Rapid Behavioural Antidepressant Responses Nature June 15, 2011
and 2 more in the library