Semaphorin 3A-mediated perineuronal nets formation incubates depressive-like behaviors in male mice via activating parvalbumin-expressing interneurons

Mol Psychiatry. 2025 Sep 10. doi: 10.1038/s41380-025-03239-y. Online ahead of print.

ABSTRACT

Dysfunction of parvalbumin-expressing interneurons (PV-INs) in the cerebral cortex has been implicated in major depressive disorder. Perineuronal nets (PNNs), which encapsulate PV-INs, are considered to influence the structural and functional properties of PV-INs. Semaphorin 3A (Sema3A) is a secreted protein constituent of PNNs, but the specific roles of Sema3A in modulating PV-INs during stress remain unknown. Here, we demonstrated that Sema3A, secreted by GABAergic interneurons, contributed to the response to chronic stress in male mice. The accumulation of Sema3A interacts with PNNs and facilitates PNNs wrapping of PV-INs, leading to a decrease in inhibitory synaptic input and an increase in the excitability of PV-INs. Sema3A-mediated formation of PNNs and 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 to facilitate adaptive behavioral responses to stress.

PMID:40926092 | DOI:10.1038/s41380-025-03239-y