Effect of maternal immune activation on the kynurenine pathway in preadolescent rat offspring and on MK801-induced hyperlocomotion in adulthood: amelioration by COX-2 inhibition

Abstract

Infections during pregnancy and subsequent maternal immune activation (MIA) increase risk for schizophrenia in offspring. The progeny of rodents injected with the viral infection mimic polyI:C during gestation display brain and behavioural abnormalities but the underlying mechanisms are unknown. Since the blood kynurenine pathway (KP) of tryptophan degradation impacts brain function and is strongly regulated by the immune system, we tested if KP changes occur in polyI:C offspring at preadolescence. We also tested whether MK801-induced hyperlocomotion, a behaviour characteristic of adult polyI:C offspring, is prevented by adolescent treatment with celecoxib, a COX-2 inhibitor that impacts the KP. Pregnant rats were treated with polyI:C (4mg/kg, i.v.) or vehicle on gestational day 19. Serum levels of KP metabolites were measured in offspring of polyI:C or vehicle treated dams at postnatal day (PND) 31-33 using HPLC/GCMS. Additional polyI:C or vehicle exposed offspring were given celecoxib or vehicle between PND 35 and 46 and tested with MK801 (0.3mg/kg) in adulthood (PND>90). Prenatal polyI:C resulted in increases in the serum KP neurotoxic metabolite quinolinic acid at PND 31-33 (105%, p=0.014). In contrast, the neuroprotective kynurenic acid and its precursor kynurenine were significantly decreased (28% p=0.027, and 31% p=0.033, respectively). Picolinic acid, another neuroprotective KP metabolite, was increased (31%, p=0.014). Adolescent treatment with celecoxib (2.5 and 5mg/kg/day, i.p.) prevented the development of MK801-induced hyperlocomotion in adult polyI:C offspring. Our study reveals the blood KP as a potential mechanism by which MIA interferes with postnatal brain maturation and associated behavioural disturbances and emphasises the preventative potential of inflammation targeting drugs.

Keywords: Adolescence; COX-2 inhibition; Celecoxib; Kynurenine pathway; Maternal immune activation; PolyI:C; Prevention; Wistar rat.