Background: 30-50% of autistic children show increased blood levels of the neurotransmitter serotonin, despite depressed serotonergic function in the central nervous system (CNS). Serotonin is synthesized in the CNS and in the gut from the essential amino acid tryptophan, which can be also degraded into kynurenine. Blood serotonin derives from the gut and, in contrast to tryptophan, cannot cross the blood-brain barrier (BBB).
Objectives: We investigated alterations of the tryptophan-kynurenine catabolic pathway in autistic children.
Methods: Blood (N=22) and cerebrospinal fluid (CSF) (N=11) samples were collected from autistic children (AUT) ages 2-6 years. Blood samples from age-matched typically-developing children (TD; N=16) and from children with developmental delay not associated with autism (DD; N=4) were also collected. We measured plasma and CSF tryptophan and kynurenine, as well as leukocyte mRNA expression of the tryptophan-to-kynurenine catabolizing enzyme indoleamine 2,3 dioxygenase (IDO) and of its inducer interferon-g.
Results: Plasma and CSF tryptophan were directly correlated (P=0.019), consistent with the permeability of the BBB to the amino acid. Kynurenine was undetectable in CSF (<0.04mmol/L). Plasma tryptophan was significantly reduced in the AUT, but not DD, groups compared to TD (p=4.6x10^-5 and 5.1x10^-5). Surprisingly, plasma kynurenine levels were also reduced in the AUT group compared to TD (p=0.003). No differences were observed for IDO and interferon-g expression, suggesting that the reduction of tryptophan was not due to IDO-mediated degradation.
Conclusions: Low plasma tryptophan may result in its limited availability for serotonin production in the CNS, negatively affecting serotonergic function in young children with autism. Reduced plasma kynurenine suggests that tryptophan may be preferentially diverted to other pathways in the periphery, most likely toward gut-associated production of serotonin, which does not cross the BBB nor contribute to serotonergic function in the CNS.