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Autism Res. 2016 Jun;9(6):621-31. doi: 10.1002/aur.1565. Epub 2015 Oct 24.

Altered kynurenine pathway metabolism in autism: Implication for immune-induced glutamatergic activity.

Author information

1
Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, NSW, Australia.
2
Department of Food Science and Nutrition, Sultan Qaboos University, Sultanate of Oman.
3
Ageing and Dementia Research Group, Sultan Qaboos University, Sultanate of Oman.
4
Department of Statistics, Faculty of Science and Engineering, Macquarie University, NSW, Australia.
5
Department of Family Medicine and Public Health, Sultan Qaboos University, Sultanate of Oman.
6
Department of Behavioral Medicine, Sultan Qaboos University, Sultanate of Oman.

Abstract

Dysfunction of the serotoninergic and glutamatergic systems is implicated in the pathogenesis of autism spectrum disorder (ASD) together with various neuroinflammatory mediators. As the kynurenine pathway (KP) of tryptophan degradation is activated in neuroinflammatory states, we hypothesized that there may be a link between inflammation in ASD and enhanced KP activation resulting in reduced serotonin synthesis from tryptophan and production of KP metabolites capable of modulating glutamatergic activity. A cross-sectional study of 15 different Omani families with newly diagnosed children with ASD (n = 15) and their age-matched healthy siblings (n = 12) was designed. Immunological profile and the KP metabolic signature were characterized in the study participants. Our data indicated that there were alterations to the KP in ASD. Specifically, increased production of the downstream metabolite, quinolinic acid, which is capable of enhancing glutamatergic neurotransmission was noted. Correlation studies also demonstrated that the presence of inflammation induced KP activation in ASD. Until now, previous studies have failed to establish a link between inflammation, glutamatergic activity, and the KP. Our findings also suggest that increased quinolinic acid may be linked to 16p11.2 mutations leading to abnormal glutamatergic activity associated with ASD pathogenesis and may help rationalize the efficacy of sulforaphane treatment in ASD. Autism Res 2016, 9: 621-631.

KEYWORDS:

autism; excitotoxicity; glutamatergic activity; kynurenine pathway; neuroinflammation; quinolinic acid

PMID:
26497015
DOI:
10.1002/aur.1565
[Indexed for MEDLINE]

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