Brain hyperserotonemia causes autism-relevant social deficits in mice.

BACKGROUND

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.

METHODS

We analyzed behavior and gene expression to unveil the causal mechanism of ASD-relevant social deficits using serotonin transporter () knockout mice.

RESULTS

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 HZ and KO mice. The expression of rather distinct sets of genes was altered in HZ and KO mice, and a substantial portion of these genes was also affected by tryptophan depletion. Tryptophan depletion in 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 gene was altered in both HZ and KO mice. expression and ASD-relevant social deficits normalized after dietary tryptophan restriction.

CONCLUSIONS

These findings reveal a 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.