The prefrontal cortex is one of the most commonly studied structures in depression. Synaptic loss and prefrontal circuits deficits have been widely described in depression physiopathology, and their restoration by antidepressant drugs is at the center of their therapeutic effect. Aims: This project aims to test the antidepressant potential of a specific manipulation of prefrontal circuits. Methods: Using the Chronic Despair Model (CDM) of depression, and the DREADDs chemogenetic technique, we counteracted the hypofrontality characteristic of a depressive-like state, and assessed the behavioural, synaptic and electrophysiological outcomes. Results: We have shown that the DREADDs stimulation of CaMKIIa-positive infralimbic neurons was sufficient to produce antidepressant effects in a variety of behavioural tests covering despair behaviour (Tail Suspension Test, Forced Swim Test) and motivation / hedonic behaviour (Sucrose Preference Test). Moreover, it restored the CDM mice deficits in excitatory synapse density. Strikingly, although no direct projections from the PFC to the hippocampus have been clearly described, the DREADDs excitation of the PFC led to a restoration of hippocampal Long-Term Potentiation (LTP), strongly impaired in CDM mice, and generally associated with positive response to antidepressant therapy. Conclusion: These results show that the localized stimulation of neuronal activity in the PFC is sufficient to produce an antidepressant effect, but also to restore deficits in distant major brain regions, such as the hippocampus. Altogether, this project highlights the therapeutic potential of brain stimulation in depression, and the role of the PFC as a major hub in depression.