Maternal immune activation with high molecular weight poly (I:C) induces selective depressive-like phenotype in adult offspring

Abstract

Maternal immune activation (MIA) during pregnancy may increase the risk for neurodevelopmental disorders such as schizophrenia and autism in offspring. Preclinical and human evidence support a potential role for MIA in the development of depressive symptoms in offspring. Among animal models of MIA, prenatal treatment with the synthetic viral mimetic polyinosinic-polycytidylic acid [poly (I:C)] is well established in studying psychotic-like and autism-like phenotypes, while its validity for modeling depressive-like behaviors remains underexplored. In this study, we assessed whether MIA, induced in rats with an injection of high molecular weight (HMW) poly (I:C), at gestational day 15, leads to a depressive-like phenotype in the offspring. In male and female offspring during adolescence and adulthood, we evaluated i) behavioral despair and anhedonia using the forced swim test (FST) and sucrose preference test (SPT); ii) the electrophysiological properties of dorsal raphe nucleus (DRN) serotonin (5-HT) neurons in vivo; iii) serum cytokine profile. We found that MIA offspring exhibited increased immobility and reduced climbing and swimming in the FST, with more pronounced effects in males, while sucrose preference remained unaltered. In vivo recordings revealed a significant increase in 5-HT neuron firing rate in MIA adult males. Peripheral cytokine analysis showed elevated IL-1α in MIA males and decreased GRO/KC levels in MIA females. In conclusion, these findings indicate that prenatal exposure to HMW poly (I:C) selectively affects stress-coping mechanisms without inducing anhedonia, modulates serotonergic signaling in a sex- dependent manner in the absence of widespread inflammatory alterations.