Prefrontal cortex molecular clock modulates development of depression-like phenotype and rapid antidepressant response in mice

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Sarrazin, David | Gardner, Wilf | Marchese, Carole | Balzinger, Martin | Ramanathan, Chockalingam | Schott, Marion | Rozov, Stanislav | Veleanu, Maxime | Vestring, Stefan | Normann, Claus | Rantamäki, Tomi | Antoine, Benedicte | Barrot, Michel | Challet, Etienne | Bourgin, Patrice | Serchov, Tsvetan

Edité par CCSD ; Nature Publishing Group -

International audience. 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 Bmal1 KO 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.

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