The effect of transient increases in kynurenic acid and quinolinic acid levels early in life on behavior in adulthood: Implications for schizophrenia

Abstract

Kynurenic acid is a tryptophan metabolite that is synthesized and released in the brain by astrocytes and acts as an antagonist of nicotinic acetylcholine receptors and N-methyl-D-aspartate glutamate receptors, both of which are critically involved in cognition as well as neural plasticity and brain development. The concentration of kynurenic acid is increased in the brains of persons with schizophrenia and this increase has been implicated in the cognitive and social impairments associated with the disease. In addition, growing evidence suggests that the increase in kynurenic acid may begin early in life. For example, exposure to influenza A virus during development results in a transient increase in kynurenic acid concentration that could disrupt normal brain development and lead to cognitive deficits later in life. Changes in kynurenic acid may thus provide a link between developmental exposure to viruses and the increased risk of subsequently developing schizophrenia. To test this, we mimicked the effects of influenza A exposure by treating rats with kynurenine, the precursor of kynurenic acid, on postnatal days 7-10. We observed a transient increase in both kynurenic acid and quinolinic acid during treatment. When rats were subsequently behaviorally tested as adults, those previously treated with kynurenine exhibited decreased social behavior and locomotor activity. In contrast, attentional function and fear conditioning were not affected. Together with other recent findings, these findings have several implications for understanding how viral-induced changes in tryptophan metabolism during development may contribute to schizophrenia-related symptoms later in life.

Adaptive and Behavioral Changes in Kynurenine 3-Monooxygenase Knockout Mice: Relevance to Psychotic Disorders

“…This finding is in agreement with reports documenting impaired social behavior in rats after the administration of KYNA’s brain-penetrable bioprecursor kynurenine during early postnatal development or adolescence (53, 54). Of note in this context, a deficit in social interactions is also seen in inbred BTBR T+tf/J mice, which likely have a compromised Kmo gene and display an array of autism-like behavioral phenotypes (55).…”

Continuous kynurenine administration during the prenatal period, but not during adolescence, causes learning and memory deficits in adult rats

“…This included intermittent systemic kynurenine injections between PD 27 and PD 53, and behavioral testing on PD 61 (Akagbosu et al 2010; Trecartin and Bucci 2011), repeated kynurenine injections on PD 7–16 (Holtze et al 2010) or PD 7–10 (Iaccarino et al 2013) with testing in adulthood, and our own perinatal kynurenine administration paradigm (Alexander et al 2013; Pocivavsek et al 2012). In all these studies, as well as after transient elevation of brain KYNA levels following early postnatal viral infection (Asp et al 2010), adult animals exhibited impairments in a variety of cognitive or social behaviors.…”

Elevated kynurenine pathway metabolism during neurodevelopment: Implications for brain and behavior

“…Sequential systemic injections of kynurenine from PND 7 to 16 in mice (Liu et al, 2014) or PND 7 to 10 in rats (Iaccarino et al, 2013) result in enhanced amphetamine-induced locomotor activity and deficits in social interaction, respectively. Intermittent treatment of adolescent rats with systemic injections of kynurenine results in impaired hippocampal-mediated cognition, assessed by novel object recognition and contextual fear memory, as well as dysfunctional social interaction in adulthood (PND 61) (Akagbosu et al, 2012; Trecartin and Bucci, 2011).…”