1. Prefrontal cortex molecular clock modulates development of depression-like phenotype and rapid antidepressant response in mice.
- Author
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Sarrazin DH, Gardner W, Marchese C, Balzinger M, Ramanathan C, Schott M, Rozov S, Veleanu M, Vestring S, Normann C, Rantamäki T, Antoine B, Barrot M, Challet E, Bourgin P, and Serchov T
- Subjects
- Animals, Mice, Male, Circadian Rhythm drug effects, Mice, Inbred C57BL, Period Circadian Proteins metabolism, Period Circadian Proteins genetics, Disease Models, Animal, Phenotype, Neuronal Plasticity drug effects, Receptors, AMPA metabolism, Receptors, AMPA genetics, Nuclear Receptor Subfamily 1, Group D, Member 1 metabolism, Nuclear Receptor Subfamily 1, Group D, Member 1 genetics, Homer Scaffolding Proteins metabolism, Homer Scaffolding Proteins genetics, Neurons metabolism, Neurons drug effects, Prefrontal Cortex metabolism, Prefrontal Cortex drug effects, Depression drug therapy, Depression metabolism, Depression genetics, Antidepressive Agents pharmacology, Ketamine pharmacology, Mice, Knockout, ARNTL Transcription Factors metabolism, ARNTL Transcription Factors genetics
- 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., (© 2024. The Author(s).)
- Published
- 2024
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