Neonatal LPS exposure results in ATP8A2 down-regulation in the prefrontal cortex and depressive-like behaviors in mice through increasing IFN-γ level

Neonatal lipopolysaccharide (LPS) exposure can lead to depressive-like behaviors in mice through inducing pro-inflammatory cytokines including interferon(IFN)-{gamma}. ATP8A2 is a phospholipid transporter located on the cell membrane. Studies have shown that the decrease in ATP8A2 expression in the prefrontal cortex (PFC) is associated with depressive behavior. Moreover, it has been reported that IFN-{gamma} could reduce ATP8A2 expression in non-neuronal cells. These findings prompted us to hypothesize that neonatal LPS exposure might induce ATP8A2 down-regulation in PFC in mice by increasing the IFN-{gamma} level. Mice pups consisting approximately evenly of both sexes were intraperitoneally injected with 3 doses of LPS (50 g/kg body weight for each dose) on postnatal day (PND5), PND7 and PND9. Here, we first found that PFC ATP8A2 expression decreased significantly and transiently till ten days after neonatal LPS exposure with the lowest level at two days after it. Moreover, a negative correlation of PFC ATP8A2 expression was found with the PFC level of IFN-{gamma}, rather than the other LPS-induced pro-inflammatory cytokines. Using anti-IFN-{gamma} neutralizing mAb, IFN-{gamma} was identified as the key mediator of LPS-induced ATP8A2 down-regulation in PFC in mice. Besides, neutralizing IFN-{gamma} partially but significantly rescued the depressive-like behaviors in adulthood induced by neonatal LPS exposure. In sum, the present study showed that neonatal LPS exposure induced ATP8A2 down-regulation in PFC and depressive-like behaviors in mice through increasing the IFN-{gamma} level.