Maternal Inflammation with Elevated Kynurenine Metabolites Is Related to the Risk of Abnormal Brain Development and Behavioral Changes in Autism Spectrum Disorder

Abstract

Several studies show that genetic and environmental factors contribute to the onset and progression of neurodevelopmental disorders. Maternal immune activation (MIA) during gestation is considered one of the major environmental factors driving this process. The kynurenine pathway (KP) is a major route of the essential amino acid L-tryptophan (Trp) catabolism in mammalian cells. Activation of the KP following neuro-inflammation can generate various endogenous neuroactive metabolites that may impact brain functions and behaviors. Additionally, neurotoxic metabolites and excitotoxicity cause long-term changes in the trophic support, glutamatergic system, and synaptic function following KP activation. Therefore, investigating the role of KP metabolites during neurodevelopment will likely promote further understanding of additional pathophysiology of neurodevelopmental disorders, including autism spectrum disorder (ASD). In this review, we describe the changes in KP metabolism in the brain during pregnancy and represent how maternal inflammation and genetic factors influence the KP during development. We overview the patients with ASD clinical data and animal models designed to verify the role of perinatal KP elevation in long-lasting biochemical, neuropathological, and behavioral deficits later in life. Our review will help shed light on new therapeutic strategies and interventions targeting the KP for neurodevelopmental disorders.

Keywords: autism spectrum disorder; interleukin-17a; kynurenine; maternal immune activation.

Figure 1

Simplified diagram of the Tryptophan (Trp) metabolism through serotonin (5-HT) and kynurenine (Kyn) pathways and direct metabolism by microorganisms. Pro-inflammatory cytokines, which upregulate enzyme activity of indoleamine 2,3-dioxygenase1 (IDO1) and tryptophan 2,3-dioxygenase (TDO), are highlighted by “+”. The triangle shows enzymes. Trapezoid with dotted line shows intestinal microbial pathway. TPH, tryptophan hydroxylase; KMO, kynurenine 3-monooxygenase; KATs, kynurenine aminotransferases; KYNU, kynureninase; QPRT, quinolinic phosphoribosyltransferase; TNA, tryptophanase; AraT, aromatic amino acid aminotransferase; TMO, tryptophan 2-monooxygenase. * Aryl hydrocarbon receptor (AhR) ligands, ** potential AhR ligand.

Figure 2

Summary of the review.