REVERSE phenotyping-Can the phenotype following constitutive Tph2 gene inactivation in mice be transferred to children and adolescents with and without adhd?
Brain Behav
; 11(5): e02054, 2021 05.
Article
em En
| MEDLINE
| ID: mdl-33523602
ABSTRACT
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.Palavras-chave
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Base de dados:
MEDLINE
Assunto principal:
Transtorno do Deficit de Atenção com Hiperatividade
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article