Lipopolysaccharide-Induced Depression and Neuroinflammatory Responses: Differential Effects on Hippocampus and Prefrontal Cortex in Mice

BACKGROUND: Lipopolysaccharide (LPS) administration in mice is a widely used model for studying inflammation-associated depression. However, the mechanisms underlying LPS-induced behavioral and neuroinflammatory changes in different brain regions remain unclear. AIM: This study aimed to investigate behavioral, cellular, and molecular changes induced by chronic-interval LPS treatment in two brain regions implicated in depression: the hippocampus and the prefrontal cortex (PFC). METHODS: The study was conducted on adult male mice (2–3 months old, 25–35 g, n=29), which were divided into control and experimental groups. Inclusion criteria were based on age and body weight, while animals with visible pathologies were excluded. The experimental design included a two-phase LPS administration protocol (1 mg/kg, intraperitoneally) with a 7-day interval. During the first phase, behavioral assessments were performed, while in the second phase, tissue samples were collected for molecular and histological analyses. Behavioral assessment included the Open Field Test (general activity and anxiety-like behavior), the Tail Suspension Test, the Sucrose Preference Test (anhedonia), and the Y-Maze Test (spatial working memory). Molecular and cellular changes were analyzed using real-time PCR, immunohistochemistry, histological methods, and experiments on primary glial cell cultures. RESULTS: LPS-treated mice exhibited depression-like behavior, including anhedonia, increased immobility, reduced locomotor activity, and memory deficits. Elevated expression of proinflammatory cytokines (TNF-α, IL-1β) was detected in both the spleen and brain, with distinct regional patterns. LPS increased blood-brain barrier permeability markers and significantly elevated the number of mast cells, particularly in the hippocampus. Microglial activation was observed in both regions, with a shift toward an amoeboid phenotype. Glutamatergic signaling was altered, with downregulation of glutamate transporters (GLT-1) and glutamine synthetase in the hippocampus, suggesting impaired glutamate buffering. In vitro, LPS induced microglial activation, which was reversed by fibroblast growth factor 2 (FGF2). CONCLUSION: LPS-induced neuroinflammation differentially affected the hippocampus and PFC, with the hippocampus appearing more vulnerable. FGF2 reversed LPS-induced microglial activation, highlighting its potential as a therapeutic target for neuroinflammation-related depression.