Abstract
Deleterious mutations in patchd1 domain containing 1 (PTCHD1) gene have been identified in patients with intellectual disability and/or autism spectrum disorder (ASD). To clarify the causal relationship between Ptchd1 deficiency and behavioral defects relevant to neurodevelopmental disorders, we generated global Ptchd1 knockout (KO) mice. Ptchd1 KO mice displayed hyperlocomotion, increased impulsivity, and lower recognition memory, which resemble attention-deficit hyperactivity disorder (ADHD)-like behaviors. Acute or chronic treatment with atomoxetine ameliorated almost all behavioral deficits in Pthcd1 KO mice. We next determined possible involvement of the kynurenine pathway (KP) metabolites in neurodevelopmental disorders in Ptchd1 KO mice and assessed the potential of KP metabolites as biomarkers for ADHD and/or ASD. Ptchd1 KO mice showed drastic changes in KP metabolite concentrations in the serum and the brain, indicating that the activated KP is associated with ADHD-like behaviors. Our findings indicate that Ptchd1 KO mice can be used as an animal model of human ADHD and/or ASD, and KP metabolites are potential diagnostic biomarkers for neurodevelopmental disorders.
Highlights
Deleterious mutations in patchd1 domain containing 1 (PTCHD1) gene have been identified in patients with intellectual disability and/or autism spectrum disorder (ASD)
In this study examined the role of kynurenine pathway (KP) metabolites in Ptchd1 KO mice to elucidate biological mechanisms underlying attention-deficit hyperactivity disorder (ADHD) and/or ASD, and the findings would provide some insights into the development of new predictive biomarkers for these neurodevelopmental disorders
The existence of hyperactivity/inattention in ASD patients is diagnosed as ASD comorbid with ADHD
Summary
Deleterious mutations in patchd domain containing 1 (PTCHD1) gene have been identified in patients with intellectual disability and/or autism spectrum disorder (ASD). Recent genetic studies have revealed a substantial overlap in risk genes in these two disorders5–7 Both disorders are affected by several environmental risk factors, including prenatal immune challenge and maternal lifestyle factors, such as smoking, alcohol, and drug use, during the prenatal period. Several studies from genomics to metabolomics, as well as those including measurements of monoamine (e.g., dopamine [DA], serotonin [5-HT], and noradrenaline [NA]), hormone (e.g., cortisol and oxytocin), and neurotrophic factor (e.g., brain-derived neurotrophic factor [BDNF]) levels in the plasma, have been performed to identify potentially predictive peripheral and genetic biomarkers for ADHD and ASD18. In this study examined the role of KP metabolites in Ptchd KO mice to elucidate biological mechanisms underlying ADHD and/or ASD, and the findings would provide some insights into the development of new predictive biomarkers for these neurodevelopmental disorders
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