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

Rosa Savino, Marco Carotenuto, Anna Nunzia Polito, Sofia Di Noia, Marzia Albenzio, Alessia Scarinci, Antonio Ambrosi, Francesco Sessa, Nicola Tartaglia, Giovanni Messina, Rosa Savino, Marco Carotenuto, Anna Nunzia Polito, Sofia Di Noia, Marzia Albenzio, Alessia Scarinci, Antonio Ambrosi, Francesco Sessa, Nicola Tartaglia, Giovanni Messina

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.

Keywords: KYNA (kynurenic acid); Kynurenine pathway; QUIN (quinolinic acid); autism spectrum disorder; immune deregulation; microglia; mitochondrial disorder; neuroinflammation; oxidative stress; tryptophan catabolites.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Figure 1
Figure 1
KYNUNERINE PATHWAY: indole-2,3-dioxygenase (IDO) and Tryptophan-2,3-dioxygenase (TDO) lead to Kynurenine synthesis from Tryptophan (TRP), which can be metabolized via two distinct pathways: the neuroprotective kynurenic acid (KYNA) branch via the KYN amino transferase enzyme (KAT), and the neurotoxic branch leading to the production of 3-hydroxy-L-KYN (3-HK) and quinolinic acid (QUIN).
Figure 2
Figure 2
Inflammation significantly shifts tryptophan metabolism to Kynurenine production by activation of activate indole-2,3-dioxygenase (IDO) and Kynurenine monooxygenase (KMO) microglial enzymes. Quinolinic acid (QUIN) is involved in neurotoxicity since it activates N-methyl-D-aspartate (NMDA) receptors, increases neuronal activity, and elevates intracellular calcium concentrations. This leads to the consequent impairment of cytoskeleton homeostasis, decrease of mitochondrial function and finally cell death induction. As an NMDA agonist, it increases neuronal glutamate release, inhibits its uptake by astrocytes, and inhibits astroglial glutamine synthetase leading to excessive microenvironmental glutamate concentrations. In addition, QUIN contributes to free radical generation and oxidative stress.
Figure 3
Figure 3
Kynurenine (KP) as a crossroad between disrupted routes and pathophysiological conditions that are Autism Spectrum Disorder (ASD) related.
Figure 4
Figure 4
Therapeutic targeting of KP.

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