Dentate Gyrus ERK1/2-BDNF Signaling is Required for the Antidepressant Effect of Microglial Stimulation in a Male Mouse Model of Depression Induced by Adolescent Nicotine Exposure.

Authors

Wei Ji, Shulin Wu, Minxiu Ye, Lin Zhang, Jin Hong, Lin Yan, Hainan Pan, Chao Huang, Yi Zhang, Hui Wang

Published in

Neurochemical research. Volume 51. Issue 3. Jun 15, 2026. Epub Jun 15, 2026.

Abstract

Adolescent nicotine exposure can reduce microglial populations in the adult mouse dentate gyrus, a change causally linked to early-stage microglial hyper-activation and reversible by treatment with low-dose lipopolysaccharide (LPS). However, the mechanisms by which LPS mediates this reversal remain unclear. Here, we identify a previously unrecognized requirement for dentate gyrus extracellular signal-regulated kinase 1/2 (ERK1/2)-brain-derived neurotrophic factor (BDNF) signaling in this process, distinct from but mechanistically parallel to our previous findings in chronic stress models. We show that low-dose LPS administration restored dorsal dentate gyrus BDNF levels reduced by adolescent nicotine exposure, and its antidepressant effects in adult mice previously exposed to nicotine during adolescence were abolished by intra-hippocampal delivery of a BDNF-neutralizing antibody, administration of the TrkB antagonist K252a, or introduction of the BDNF Val68Met loss-of-function mutation. Additionally, low-dose LPS reversed the decreased phospho-ERK1/2 in the dorsal dentate gyrus of adult mice with a history of adolescent nicotine exposure. Inhibition of ERK1/2 by SL327 prevented the reversal effect of LPS on adolescent nicotine exposure-induced depression-like behaviors and decrease in BDNF levels, suggesting that ERK1/2 functions upstream of BDNF signaling in mediating the antidepressant effect of LPS. When microglia were inhibited by minocycline, the beneficial effects of LPS, including the amelioration of depression-like behaviors and the up-regulation of dentate gyrus p-ERK1/2 and BDNF, were eliminated. These findings indicate that the antidepressant action of low-dose LPS in a mouse model of depression resulting from adolescent nicotine exposure requires intact microglial function and depends on ERK1/2-BDNF signaling within the dorsal dentate gyrus.

PMID:
42295462
Bibliographic data and abstract were imported from PubMed on 15 Jun 2026.

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