A hidden mark of a troubled past: neuroimaging and transcriptomic analyses reveal interactive effects of maternal immune activation and adolescent THC exposure in the absence of overt behavioural disruptions
Maternal exposure to infections during gestation has been shown to predispose individuals to develop schizophrenia. In addition, clinical data suggest that cannabis use could trigger disease onset in vulnerable individuals. However, the question of causality remains unclear. To shed light on this issue, we used a rat model of maternal immune activation combined with exposure to increasing doses of THC during adolescence in animals of both sexes. We studied several behaviours at adulthood that resemble specific symptoms of schizophrenia (working memory impairments, sensorimotor gating deficits, alterations in social behaviour, anhedonia, and potential alterations in implicit learning). In addition, we performed positron emission tomography on two time points to search for affected brain regions and then obtained brain samples of one of these affected regions (the orbitofrontal cortex) to carry out RNAseq analyses, which were also performed in peripheral blood mononuclear cells. Strikingly, while there were no overt behavioural disruptions, our PET scans revealed several brain alterations that relied on the combination of both hits. Maternal immune activation affected glutamatergic and serotoninergic genes, and the combination with THC shifted their expression from down-regulation to up-regulation. In the peripheral cells, interactive effects were observed on inflammatory pathways and some genes are proposed as biomarkers of the disease. These results suggest that the combination of these two vulnerability factors leaves a lingering mark on the body which could predispose to the disease, even before behavioural alterations manifest. Overall design: We studied the effects of maternal exposure to LPS/saline,  adolescent exposute to increasing doses of THC (or vehicle) and the sex of the animals.  Samples are blood peripheral mononuclear cells RNA or orbitofrontal cortex RNA 17:33from rats extracted with RNAeasy Qiagen kit.