Indoleamine 2,3‐dioxygenase 2 deficiency associates with autism‐like behavior via dopaminergic neuronal dysfunction

Abstract

Indoleamine 2,3‐dioxygenase 2 (IDO2) is an enzyme of the tryptophan–kynurenine pathway that is constitutively expressed in the brain. To provide insight into the physiological role of IDO2 in the brain, behavioral and neurochemical analyses in IDO2 knockout (KO) mice were performed. IDO2 KO mice showed stereotyped behavior, restricted interest and social deficits, traits that are associated with behavioral endophenotypes of autism spectrum disorder (ASD). IDO2 was colocalized immunohistochemically with tyrosine‐hydroxylase‐positive cells in dopaminergic neurons. In the striatum and amygdala of IDO2 KO mice, decreased dopamine turnover was associated with increased α‐synuclein level. Correspondingly, levels of downstream dopamine D1 receptor signaling molecules such as brain‐derived neurotrophic factor and c‐Fos positive proteins were decreased. Furthermore, decreased abundance of ramified‐type microglia resulted in increased dendritic spine density in the striatum of IDO2 KO mice. Both chemogenetic activation of dopaminergic neurons and treatment with methylphenidate, a dopamine reuptake inhibitor, ameliorated the ASD‐like behavior of IDO2 KO mice. Sequencing analysis of exon regions in IDO2 from 309 ASD samples identified a rare canonical splice site variant in one ASD case. These results suggest that the IDO2 gene is, at least in part, a factor closely related to the development of psychiatric disorders.