Analyzing the Potential Biological Determinants of Autism Spectrum Disorders: From Neuroinflammation to Kynurenines Pathway

Abstract

Autism Spectrum Disorder etiopathogenesis is still unclear and no effective preventive and treatment measures have been identified. Research has focused on the potential role of neuroinflammation and 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, also, have identified some important polymorphisms in chromosome loci related to 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 kynurenine pathway with increase in neurotoxic metabolites and excitotoxicity, causing long-term changes in glutamatergic system, trophic support and synaptic function. Furthermore, overactivation of kynurenine’s branch induces depletion of melatonin and serotonin worsening ASD symptoms. In this scenario, kynurenine pathway appears as a pharmacological target to treat and prevent ASD. Thus, in genetically predisposed subjects aberrant neurodevelopment may derives from a complex interplay between inflammatory process, mitochondrial dysfunction, oxidative stress and kynurenine pathway overexpression. To validate previous hypothesis a new translational research approach is necessary.

Transcriptional regulation of neonatal neural stem cells is a determinant of social behavior

“…The copyright holder for this preprint this version posted November 13, 2021. ; https://doi.org /10.1101/10. /2021 enzyme in the catabolism of tryptophan in the kynurenine pathway, the downregulation of which has been implicated in ASD (31). We additionally tested Btg1, as it was identified in MANGO (Table S1-2) but not in databases of neurodevelopmental disorders (see Table S1-3; S1-4).…”