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 and Tsvetan Serchov ()
Additional contact information
David H. Sarrazin: Institute of Cellular and Integrative Neurosciences (INCI) UPR 3212
Wilf Gardner: Institute of Cellular and Integrative Neurosciences (INCI) UPR 3212
Carole Marchese: Institute of Cellular and Integrative Neurosciences (INCI) UPR 3212
Martin Balzinger: Institute of Cellular and Integrative Neurosciences (INCI) UPR 3212
Chockalingam Ramanathan: Medical Faculty
Marion Schott: Institute of Cellular and Integrative Neurosciences (INCI) UPR 3212
Stanislav Rozov: University of Helsinki
Maxime Veleanu: University of Freiburg
Stefan Vestring: University of Freiburg
Claus Normann: University of Freiburg
Tomi Rantamäki: University of Helsinki
Benedicte Antoine: Centre de Recherches St‐Antoine (CRSA)
Michel Barrot: Institute of Cellular and Integrative Neurosciences (INCI) UPR 3212
Etienne Challet: Institute of Cellular and Integrative Neurosciences (INCI) UPR 3212
Patrice Bourgin: Institute of Cellular and Integrative Neurosciences (INCI) UPR 3212
Tsvetan Serchov: Institute of Cellular and Integrative Neurosciences (INCI) UPR 3212

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-51716-9

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