Postnatal Lipopolysaccharide Exposure Impairs Adult Neurogenesis and Causes Depression-like Behaviors Through Astrocytes Activation Triggering GABAA Receptor Downregulation.

• Postnatal LPS exposure increases the depression-like behaviors of adult mice. • Postnatal LPS exposure impairs adult neurogenesis via decreasing GABA A R expression. • Astrocyte activation results in LPS-induced downregulation of BDNF/TrkB and GABA A R. • TAK-242 corrects the effect of LPS on neurogenesis and behavior via GABA system. Growing evidence indicates that early-life inflammation has adverse effects on adult hippocampal neurogenesis and GABA system. Based the report that hippocampal GABA system is a key modulator in adult hippocampal neurogenesis, the aim of this study was to investigate whether and how early inflammation affects GABAergic system resulting in the alterations of adult hippocampal neurogenesis and related behaviors. Neonatal mice received a daily subcutaneous injection of lipopolysaccharide (LPS, 50 μg/kg) or saline on postnatal days (PND) 3–5. Behavioral tests were used to explore LPS-induced depression-like behaviors of adult mice. Immunohistochemistry staining and western blot were employed to detect adult neurogenesis, GABAergic system, glia activation and BDNF-TrkB pathway in the hippocampus. LPS-treated mice developed a depression phenotype with the inhibited maturation of hippocampal newborn neurons in adulthood. Compared with controls, LPS mice showed a decreased expression of GABAA receptor (GABA A R) protein. GABA A R agonist phenobarbital could rectify the decrease of BrdU+/NeuN+ cells in LPS mice. Additionally, postnatal LPS treatment resulted in the activation of astrocytes and the increase expression of toll-like receptor 4 (TLR4) in the second postnatal week and the downregulation of BDNF-TrkB pathway in adulthood. The treatment with TLR4 inhibitor TAK-242 restored the decrease of BrdU+/NeuN+ cells and depression-like behaviors in LPS mice via improving GABA A R. The results indicate that postnatal LPS exposure impairs adult hippocampal neurogenesis and causes depression-like behaviors through early astrocytes activation triggering the later GABA A R downregulation. [ABSTRACT FROM AUTHOR]