title: Behavioral disturbances in adult mice following neonatal virus infection or kynurenine treatment--role of brain kynurenic acid.
abstract: 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.
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Xi-Cong
authors.initials: XC
authors.lastname: Liu
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Holtze
authors.affiliation: Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.
authors.forename: Susan B
authors.initials: SB
authors.lastname: Powell
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Niccolò
authors.initials: N
authors.lastname: Terrando
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Markus K
authors.initials: MK
authors.lastname: Larsson
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Persson
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Sara K
authors.initials: SK
authors.lastname: Olsson
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Funda
authors.initials: F
authors.lastname: Orhan
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Kegel
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Linnea
authors.initials: L
authors.lastname: Asp
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Michel
authors.initials: M
authors.lastname: Goiny
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Lilly
authors.initials: L
authors.lastname: Schwieler
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Göran
authors.initials: G
authors.lastname: Engberg
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Håkan
authors.initials: H
authors.lastname: Karlsson
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden. Electronic address: sophie.erhardt@ki.se.
authors.forename: Sophie
authors.initials: S
authors.lastname: Erhardt
mesh_terms: D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000378:metabolism*; D001923:Brain Chemistry / Q000187:drug effects; D003213:Conditioning, Psychological / Q000187:drug effects; D004298:Dopamine / Q000032:analysis; D015259:Dopamine Agents / Q000494:pharmacology; D005260:Female; D009980:Influenza A virus; D007736:Kynurenic Acid / Q000378:metabolism*; D007737:Kynurenine / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D009976:Orthomyxoviridae Infections / Q000378:metabolism / Q000503:physiopathology*
chemical_list: D015259:Dopamine Agents; D007737:Kynurenine; D000661:Amphetamine; D007736:Kynurenic Acid; D004298:Dopamine
keywords: Amphetamine; Immune activation; Kynurenine; Locomotor activity; Microdialysis; Neurodevelopment; Postnatal; Prepulse inhibition; Schizophrenia