Impact of mild prenatal LPS-induced inflammation and postnatal stress on synaptic plasticity and neuroimmune responses in the prefrontal cortex of adult male mice

Mild maternal immune activation (MIA) alone has been reported to exert minimal effects on the newborn brain, but when combined with postnatal stress (PS), it can trigger significant and, lasting neuro developmental changes. This study investigated the effects of MIA, alone and in combination with PS, on synaptic plasticity and molecular pathways in the prefrontal cortex, with a focus on potential links to neurodevelopmental disorders. Pregnant mice received an intraperitoneal injection of lipopolysaccharide (LPS, 50 μg/kg) or sterile normal saline on gestational day 17 (GD17). Offspring were exposed to prepubertal stress or no stress from postnatal days 30–38. Two male pups per litter (totally n = 6/ per group) were randomly selected at postnatal day 56 day for prefrontal cortex analysis. Histological, structural, and molecular analyses were conducted, including immunohistochemistry and gene expression analysis. The LPS+Stress group revealed a significant (P < 0.05) reduction in astrocyte-related synaptic cells compared with the LPS, stress control groups. Expression levels of synaptic plasticity-related proteins and genes (BDNF, GAP-43, N-cadherin, synapsin-1, and GFAP) were significantly (P < 0.05) reduced in the LPS+Stress group compared to all other groups. While MIA and PS independently induced subtle synaptic and inflammatory changes, their combined effects were significantly amplified, leading to aberrant molecular expression critical for synaptic function. These findings suggest that the combined effects of mild MIA and PS may exacerbate synaptic and inflammatory dysregulation, potentially increasing susceptibility to neurodevelopmental disorders. Future research should explore potential therapeutic strategies to mitigate the synergistic effects of MIA and PS on neurodevelopment.