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

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.

Automated summary

Several studies have shown that genetic and environmental factors play significant roles in the development and progression of neurodevelopmental disorders. Maternal immune activation during pregnancy is considered a major environmental factor in this process. The activation of the kynurenine pathway following neuro-inflammation generates neuroactive metabolites that can affect brain functions and behaviors. Investigating the role of kynurenine pathway metabolites during neurodevelopment can provide valuable insights into the pathophysiology of neurodevelopmental disorders. Evaluating clinical data and animal models, this review examines the impact of perinatal kynurenine pathway elevation on long-term biochemical, neuropathological, and behavioral deficits, with the aim of informing new therapeutic strategies and interventions for these disorders.