Behavioral disturbances in adult mice following neonatal virus infection or kynurenine treatment – Role of brain kynurenic acid

Highlight
• Induction of the kynurenine pathway in early life is associated with long-lasting effects with regard to behavior and neurotransmission related to schizophrenia.

Exposure to infections in early life is considered a risk-factor for developing schizophrenia. Recently we reported that a neonatal CNS infection with influenza A virus in mice resulted in a transient induction of the brain kynurenine pathway, and subsequent behavioral disturbances in immune-deficient adult mice. The aim of the present study was to investigate a potential role in this regard of kynurenic acid (KYNA), an endogenous antagonist at the glycine site of the N-methyl-d-aspartic acid (NMDA) receptor and at the cholinergic α7 nicotinic receptor. C57BL/6 mice were injected i.p. with neurotropic influenza A/WSN/33 virus (2400 plaque-forming units) at postnatal day (P) 3 or with l-kynurenine (2 × 200 mg/kg/day) at P7–16. In mice neonatally treated with l-kynurenine prepulse inhibition of the acoustic startle, anxiety, and learning and memory were also assessed. Neonatally infected mice showed enhanced sensitivity to d-amphetamine-induced (5 mg/kg i.p.) increase in locomotor activity as adults. Neonatally l-kynurenine treated mice showed enhanced sensitivity to d-amphetamine-induced (5 mg/kg i.p.) increase in locomotor activity as well as mild impairments in prepulse inhibition and memory. Also, d-amphetamine tended to potentiate dopamine release in the striatum in kynurenine-treated mice. These long-lasting behavioral and neurochemical alterations suggest that the kynurenine pathway can link early-life infection with the development of neuropsychiatric disturbances in adulthood.