Analyzing the Potential Biological Determinants of Autism Spectrum Disorder: From Neuroinflammation to the Kynurenine Pathway

Abstract

Autism Spectrum Disorder (ASD) etiopathogenesis is still unclear and no effective preventive and treatment measures have been identified. Research has focused on the potential role of neuroinflammation and the Kynurenine pathway; here we review the nature of these interactions. Pre-natal or neonatal infections would induce microglial activation, with secondary consequences on behavior, cognition and neurotransmitter networks. Peripherally, higher levels of pro-inflammatory cytokines and anti-brain antibodies have been identified. Increased frequency of autoimmune diseases, allergies, and recurring infections have been demonstrated both in autistic patients and in their relatives. Genetic studies have also identified some important polymorphisms in chromosome loci related to the human leukocyte antigen (HLA) system. The persistence of immune-inflammatory deregulation would lead to mitochondrial dysfunction and oxidative stress, creating a self-sustaining cytotoxic loop. Chronic inflammation activates the Kynurenine pathway with an increase in neurotoxic metabolites and excitotoxicity, causing long-term changes in the glutamatergic system, trophic support and synaptic function. Furthermore, overactivation of the Kynurenine branch induces depletion of melatonin and serotonin, worsening ASD symptoms. Thus, in genetically predisposed subjects, aberrant neurodevelopment may derive from a complex interplay between inflammatory processes, mitochondrial dysfunction, oxidative stress and Kynurenine pathway overexpression. To validate this hypothesis a new translational research approach is necessary.

DNA Methylation of PGC-1α Is Associated With Elevated mtDNA Copy Number and Altered Urinary Metabolites in Autism Spectrum Disorder

“…Altered BCAA metabolism has also been linked to oxidative stress resulting from perturbed NAD + /NADH redox ratios ( Esterhuizen et al, 2017 ). Of note, mtDNA copy number correlated significantly with the direct precursor of de novo NAD + synthesis, QA ( p = 0.008), which is a neurotoxin ( Notarangelo and Pocivavsek, 2017 ) that is also implicated in ASD etiology ( Savino et al, 2020 ). NAD + has also been identified as a metabolic link between changes in mtDNA copy number, methionine metabolism and DNA methylation ( Lozoya et al, 2018 ).…”

The Brain-Gut-Microbiome System: Pathways and Implications for Autism Spectrum Disorder

“…The KYN pathway, also derived from tryptophan and modulated by gut microbes, largely depends on indoleamine-2,3-dioxygenase (IDO) and, to a lesser degree, tryptophan-2, 3-dioxygenase (TDO) for metabolization [78]. IDO, expressed in all body tissues, is typically activated in the presence of pro-inflammatory cytokines, whereas TDO, expressed primarily in liver tissues, is activated by glucocorticoids [78,79]. Once transformed from tryptophan, KYN metabolizes into two downstream metabolites, neuroprotective kynurenic acid (KA) and neurotoxic quinolinic acid (QA) [78].…”

Palmitoylethanolamide and Its Biobehavioral Correlates in Autism Spectrum Disorder: A Systematic Review of Human and Animal Evidence

“…This is the first systematic review of all studies exploring the biobehavioral correlates of palmitoylethanolamide (PEA) in autism spectrum disorder (ASD) in humans and animals. Previous reviews have mainly addressed the potential role of neuroinflammation and altered glutamate signaling in ASD etiopathogenesis, indicating that, in subjects with genetic predispositions, atypical neurodevelopment may arise from a complex interplay between (neuro)inflammatory processes, mitochondrial dysfunction, oxidative stress and altered expression of glutamate signaling [ 35 ]. Interestingly, research evidence converges on the crucial role of exogenous cannabinoids and endocannabinoids in modulating such neurobiological systems, including neuroinflammation [ 12 ] and glutamate neurotransmission [ 13 ].…”