Semaphorin 3A-Mediated Perineuronal Nets Formation Incubates Depressive-like Behaviors in Male Mice via Activating Parvalbumin Expressing Interneurons

摘要

Objective: Neuroimaging modalities have identified structural and functional alterations in the prefrontal cortex(PFC) of depressed patients. However, the molecular mechanisms underlying synaptic dysfunction in the PFC of patients with depression remain poorly understood. Semaphorin 3A(Sema3A) is a secreted glycoprotein that plays a crucial role in axon guidance, dendrite development and synapse formation. This study aims to investigate the role and mechanism of Sema3A in chronic stress-induced depressive-like behaviors in male mice, focusing on its regulation of parvalbumin-expressing interneurons(PV-INs). Methods: Depressive-like behaviors were induced in C57BL/6J mice by chronic social defeat stress(CSDS). Adeno-associated viruses(AAVs) were used to overexpress or knockdown Sema3A in GABAergic or PV-INs. The perineuronal net(PNN)-degrading enzyme chondroitinase ABC(ChABC) was applied to disrupt PNN structure, and recombinant Sema3A(rSema3A) was administered intracerebrally. Whole-cell patch-clamp recording was used to measure miniature inhibitory postsynaptic currents(mIPSCs) and action potential firing in PV-INs. Results: Chronic stress exposure induced depressive-like behaviors, which were accompanied by an increased Sema3A from GABAergic expression in the PFC. Sema3A interacted with PNNs and promoted their wrapping around PV-INs. ChABC-mediated PNN degradation reversed Sema3A-induced depressive-like behaviors. Finally, Sema3A reduced inhibitory synaptic inputs to PV-INs(decreased mIPSCs frequency and amplitude) via PNNs and enhanced PV-INs excitability(increased AP firing and depolarized resting membrane potential) through activating Plexin A1 receptor. Conclusion: This study reveals a novel pathway in which chronic stress upregulates Sema3A in GABAergic interneurons, promoting PNN formation around PV-INs. This leads to reduced inhibitory input and increased PV-IN excitability, ultimately facilitating depressivelike behaviors. The Sema3A–PNN–PV-IN axis represents a potential therapeutic target for stressrelated mood disorders.

关键词

depression / semaphorin 3A / perineuronal nets / parvalbumin expressing interneurons / medial prefrontal cortex

基金资助

supported by the Foundation for the National Key R&D Program of China (2020YFA0803900 to JGC); the National Natural Science Foundation of China (82273912 to ZLH); the Innovative Research Groups of National Natural Science Foundation of China (81721005 to JGC and FW)