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21 reviewsDysfunction of parvalbumin-expressing interneurons (PV-INs) in the cerebral cortex has been implicated in major depressivedisorder. Perineuronal nets (PNNs), which encapsulate PV-INs, are considered to influence the structural and functional properties ofPV-INs. Semaphorin 3A (Sema3A) is a secreted protein constituent of PNNs, but the specific roles of Sema3A in modulating PV-INsduring stress remain unknown. Here, we demonstrated that Sema3A, secreted by GABAergic interneurons, contributed to theresponse to chronic stress in male mice. The accumulation of Sema3A interacts with PNNs and facilitates PNNs wrapping of PV-INs,1234567890();,:leading to a decrease in inhibitory synaptic input and an increase in the excitability of PV-INs. Sema3A-mediated formation of PNNsand the subsequent increase in PV-INs excitability may promote the development of depressive-like behaviors induced by stress.These results elucidate a molecular pathway in which Sema3A, a component of PNNs, dynamically governs the function of PV-INs tofacilitate adaptive behavioral responses to stress.Molecular Psychiatry;
