Unravelling the links between maternal infection, kynurenines, schizophrenia and its prevention in an animal model

Infections during pregnancy increase the risk of schizophrenia in offspring. The progeny of rodents injected with the viral infection mimic polyI:C during gestation consistently show schizophrenialike abnormalities that manifest in adolescence or early adulthood, but the mechanism by which this occurs in not known. Since the blood kynurenine pathway (KP) of tryptophan degradation impacts brain function and is strongly regulated by the immune system, we tested if changes in this pathway occur in offspring of polyIC injected mothers. Pregnant rats were treated with polyIC (4 mg/kg, i.v) or vehicle on gestational day 19. Serum levels of KP metabolites (kynurenines) were measured in offspring at postnatal days (PNDs) 31–33 (preadolescence) using HPLC/GCMS. mRNA expression of KP enzymes (KATII, KMO) were measured in the hippocampus using qPCR. Offspring were given the COX-2 inhibitor celecoxib (2.5 and 5 mg/kg/day, i.p.) from PNDs 35–46. Hyperlocomotor response to MK801 (0.3 mg/kg) was tested in adult male offspring (PNDs > 90). PolyIC offspring at PNDs 31–33 display abnormalities in serum metabolites of the KP. The neurotoxic metabolite quinolinic acid is significantly increased by 105% (p = 0.014) whereas the neuroprotectivekynurenic acid and its precursor kynurenine are significantly decreased by 28% (p = 0.027) and 31% (p = 0.033) respectively. We also find that KP metabolites in the serum strongly correlate with brain mRNA expression of KATII and KMO. Finally, early treatment with celecoxib (that impacts on the KP) prevents the development of MK-801-induced hyperlocomotion, a behaviour characteristic in adult offspring of polyIC treated mothers. Our studies (a) reveal the role of theKP as a potential mechanism by which maternal infection contributes to the genesis of a schizophrenia-like phenotypein offspring; (b) suggest that kynurenines in the blood can be used as an index of brain KP expression in "prodromal-like" phase in the model and (c) emphasise the preventive potential of drugs targeting inflammation.