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

Chai K. Lim, Musthafa M. Essa, Roberta de Paula Martins, David B. Lovejoy, Ayse A. Bilgin, Mostafa I. Waly, Yahya M. Al-Farsi, Marwan Al-Sharbati, Mohammed A. Al-Shaffae, Gilles J. Guillemin

Research output: Contribution to journalArticle

37 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)621-631
Number of pages11
JournalAutism Research
Volume9
Issue number6
DOIs
Publication statusPublished - Jun 1 2016

Keywords

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

ASJC Scopus subject areas

  • Neuroscience(all)
  • Clinical Neurology
  • Genetics(clinical)

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  • Cite this

    Lim, C. K., Essa, M. M., de Paula Martins, R., Lovejoy, D. B., Bilgin, A. A., Waly, M. I., Al-Farsi, Y. M., Al-Sharbati, M., Al-Shaffae, M. A., & Guillemin, G. J. (2016). Altered kynurenine pathway metabolism in autism: Implication for immune-induced glutamatergic activity. Autism Research, 9(6), 621-631. https://doi.org/10.1002/aur.1565