Year: 2018
Type: article
Abstract: Hyperserotonemia in the brain is suspected to be an endophenotype of autism spectrum disorder (ASD). Reducing serotonin levels in the brain through modulation of serotonin transporter function may improve ASD symptoms. We analyzed behavior and gene expression to unveil the causal mechanism of ASD-relevant social deficits using serotonin transporter ( Sert ) knockout mice. Social deficits were observed in both heterozygous knockout mice (HZ) and homozygous knockout mice (KO), but increases in general anxiety were only observed in KO mice. Two weeks of dietary restriction of the serotonin precursor tryptophan ameliorated both brain hyperserotonemia and ASD-relevant social deficits in Sert HZ and KO mice. The expression of rather distinct sets of genes was altered in Sert HZ and KO mice, and a substantial portion of these genes was also affected by tryptophan depletion. Tryptophan depletion in Sert HZ and KO mice was associated with alterations in the expression of genes involved in signal transduction pathways initiated by changes in extracellular serotonin or melatonin, a derivative of serotonin. Only expression of the AU015836 gene was altered in both Sert HZ and KO mice. AU015836 expression and ASD-relevant social deficits normalized after dietary tryptophan restriction. These findings reveal a Sert gene dose-dependent effect on brain hyperserotonemia and related behavioral sequelae in ASD and a possible therapeutic target to normalize brain hyperserotonemia and ASD-relevant social deficits.
Source: Molecular Autism
Institutions: Tokyo Metropolitan Institute of Medical Science, National Center of Neurology and Psychiatry, National Institute of Mental Health, Niigata University, University of Tokyo Hospital, The University of Tokyo, University of Toledo, National Institute on Drug Abuse, New Mexico VA Health Care System, National Institutes of Health, Kobe University
Language: English
Subfield: Cognitive Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,990
Awards: Prevention of autism by drug therapy targeting mTOR system in developing brain, Behavioral pharmacological study to develop animal model systems for creating drugs to treat autism, Investigation on the pathomechanism of autism spectrum disorder associated with hyperactivated mTOR signaling pathway, G3111881881, Crosstalk between serotonin and mTOR systems: molecular pathology in autism and its treatment, G3633835410, Genetic mechanisms underlying vulnerability to adverse side effects of opioids, G5320125313, G5720905528, Construction of treatment-resistant depression model mice concurrent with alcohol dependence, G7096221698, G725896798, G8166112982, Advanced Animal Model Support, G8742438570
OpenAlex ID: W2902384561