NPAS2 Deficiency Leads to Antidepressant‐Like Behaviors in Mice by Modulating Astrocyte‐Mediated Neuroinflammation

Major Depressive Disorder (MDD) is closely associated with neuroinflammation, but the underlying mechanisms remain to be fully elucidated. This study investigates the role of NPAS2 in mediating neuroinflammation-induced depressive-like behaviors using NPAS2 knockout (KO) mice and lipopolysaccharide (LPS) treatment. We confirmed that NPAS2 protein expression in the hippocampus was significantly increased in mice exposed to LPS or chronic unpredictable mild stress (CUMS). Moreover, in the hippocampus, NPAS2 in astrocytes is more sensitive to inflammatory stimuli than that in neurons. NPAS2 KO mice demonstrated attenuated astrocyte activation, reduced neuroinflammation associated with the inhibition of NF-κB and JAK2/STAT3 signaling pathways, and resilience to depressive- and anxiety-like behaviors. Mechanistically, the antidepressant effects in NPAS2 KO mice were mediated through the BDNF/TrkB signaling pathway, which is regulated by inflammatory factors and controls synaptic plasticity. This conclusion was supported by the reversal of these effects using the BDNF receptor antagonist k252a. These findings highlight the critical role of astrocytic NPAS2 in mediating neuroinflammation-induced depressive-like behaviors and suggest that targeting NPAS2 may represent a novel therapeutic strategy for MDD.