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.

Metabolomics of Mouse Embryonic CSF Following Maternal Immune Activation

“…Together with these existing data, our resource will contribute to a more mechanistic understanding of MIA relevant processes. In a separate approach, our resource can be used to generate hypotheses for how glutamate, a neurotransmitter already implicated in MIA neuropathology (Southey et al , 2023; Murakami et al , 2023) might exerts its effects. Our dataset could also help define metabolites with temporally restricted profiles (e.g., E12.5 only or E14.5 only), similarly to certain ions (Xu et al , 2021), thus guiding the formulation of an age-specific embryonic CSF for future ex vivo studies.…”

“…We observed differential abundance of metabolites from two metabolic pathways related to inflammation: glucocorticoids (Gaber et al , 2017) and the kynurenine pathway (Murakami et al , 2021, 2023; Cervenka et al , 2017). Glucocorticoids are anti-inflammatory and immunosuppressive, and among the most prescribed drugs for the treatment of immune and inflammatory disorders (Cruz-Topete & Cidlowski, 2014).…”

Reply to Ayoub-Charette et al. Lack of Biological Plausibility and Major Methodological Issues Cast Doubt on the Association between Aspartame and Autism. Comment on “Fowler et al. Daily Early-Life Exposures to Diet Soda and Aspartame Are Associated with Autism in Males: A Case-Control Study. Nutrients 2023, 15, 3772”

“…Aspartame and two other leading NNSs—sucralose and saccharin— have also increased oxidative stress and apoptosis in intestinal epithelial cells and increased epithelial barrier permeability [ 32 ], which would further exacerbate inflammation systemically. Inflammation itself has been reported to increase autism risk [ 33 ].…”

“…Aspartame-fed animals have also exhibited significantly increased serum concentrations of kynurenine [ 11 ], another metabolite produced by the gut microbiota which is elevated in individuals with autism [ 28 , 33 , 35 , 40 ]. Elevated kynurenine has been hypothesized to cause increased excitotoxicity and neuroinflammation [ 33 ] and to increase the risk of neuroanatomical problems characteristic of ASD, which arise during fetal brain development [ 41 ].…”

Kynurenic acid inflammatory signaling expands in primates and impairs prefrontal cortical cognition

“…( The expansion of KAT II KYNA signaling in primates may also have great relevance to perinatal inflammatory insults and the development of cortical circuits, as NMDAR are required for the creation of appropriate cortical connections 69 . Thus, expansive KYNA blockade of these receptors while cortical connections are forming may produce wideranging deficits in connectivity that could contribute to intellectual disability and other mental disorders, which may be more subtle in rodent models 70 .…”