REVERSE phenotyping-Can the phenotype following constitutive Tph2 gene inactivation in mice be transferred to children and adolescents with and without adhd?

Introduction: Experimental models of neuropsychiatric disorders, for example, ADHD, are used to mimic specific phenotypic traits of a complex human disorder. However, it remains unresolved to what extent the animal phenotype reflects the specific human trait. The null mutant mouse of the serotonin-synthesizing tryptophan hydroxylase-2 (Tph2(-/-)) gene has been proposed as experimental model for ADHD with high face validity for impulsive, aggressive, and anxious behaviors. To validate this ADHD-like model, we examined the Tph2(-/-) phenotype in humans when considering allelic variation of TPH2 function ("reverse phenotyping").Methods: 58 participants (6 females, 8-18 years) were examined, of whom 32 were diagnosed with ADHD. All participants were phenotyped for impulsivity, aggression, and anxiety using questionnaires, behavioral tests, and MRI scanning while performing the 4-choice serial reaction time task. Additionally, participants were genotyped for the TPH2 G-703T (rs4570625) polymorphism. To analyze the relation between TPH2 G-703T variants and the impulsive/aggressive/anxious phenotype, mediation analyses were performed using behavioral and MRI data as potential mediators.Results: We found that the relation between TPH2 G-703T and aggression as part of the reverse Tph2(-)/(-) phenotype was mediated by structure and function of the right middle and inferior frontal gyrus.Conclusion: At the example of trait aggression, our results support the assumption that the Tph2 null mutant mouse reflects the TPH2 G-703T-dependent phenotype in humans. Additionally, we conclude that "reverse phenotyping" is a promising method to validate experimental models and human findings for refined analysis of disease mechanisms.