Repetitive swim stress potentiates clock suppressor genes (Per2 and Cry2) and decreases positive regulators (RORs), while ketamine opposes CDM effects. Disrupted positive and negative elements affect Bmal1 expression and transcriptional activity, respectively, ultimately dysregulating Homer1a induction and modulating mechanisms of synaptic plasticity. Whereas, mPFC CaMK2a- Bmal1 KO in mPFC excitatory neurons removes its regulation of Homer1a, inhibiting both pro-depressive and antidepressant responses. Experimental manipulation mimicking negative loop potentiation (Rev-ERB agonist SR10067) suppresses Bmal1, Homer1a and AMPAR expression, with a pro-depressive effect. In contrast, antidepressant interventions (ketamine, ROR α agonist SR1078, si Per2 KD) inhibit negative and potentiate positive elements of the clock, increase Bmal1 expression and activity, ultimately driving induction of Homer1a. In turn, Homer1a induction is associated with increased markers of synaptic plasticity in the mPFC including increased AMPAR expression and elevated SWA, leading to positive effects on mood. Overall, this model describes specific changes to the local mPFC clock in response to stress and rapid antidepressant treatment, highlighting Bmal1 and Homer1a expression and subsequent plastic mechanisms as critical elements.
