Dataset Information

Adgrl3.1-deficient zebrafish show noradrenaline-mediated externalizing behaviors, and altered expression of externalizing disorder-candidate genes, suggesting functional targets for treatment.

ABSTRACT: Externalizing disorders (ED) are a cause of concern for public health, and their high heritability makes genetic risk factors a priority for research. Adhesion G-Protein-Coupled Receptor L3 (ADGRL3) is strongly linked to several EDs, and loss-of-function models have shown the impacts of this gene on several core ED-related behaviors. For example, adgrl3.1^-/- zebrafish show high levels of hyperactivity. However, our understanding of the mechanisms by which this gene influences behavior is incomplete. Here we characterized, for the first time, externalizing behavioral phenotypes of adgrl3.1^-/- zebrafish and found them to be highly impulsive, show risk-taking in a novel environment, have attentional deficits, and show high levels of hyperactivity. All of these phenotypes were rescued by atomoxetine, demonstrating noradrenergic mediation of the externalizing effects of adgrl3.1. Transcriptomic analyses of the brains of adgrl3.1^-/- vs. wild-type fish revealed several differentially expressed genes and enriched gene clusters that were independent of noradrenergic manipulation. This suggests new putative functional pathways underlying ED-related behaviors, and potential targets for the treatment of ED.

SUBMITTER: Fontana BD

PROVIDER: S-EPMC10545713 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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adgrl3.1-deficient zebrafish show noradrenaline-mediated externalizing behaviors, and altered expression of externalizing disorder-candidate genes, suggesting functional targets for treatment.

Fontana Barbara D BD Reichmann Florian F Tilley Ceinwen A CA Lavlou Perrine P Shkumatava Alena A Alnassar Nancy N Hillman Courtney C Karlsson Karl Ægir KÆ Norton William H J WHJ Parker Matthew O MO

Translational psychiatry 20231002 1

Externalizing disorders (ED) are a cause of concern for public health, and their high heritability makes genetic risk factors a priority for research. Adhesion G-Protein-Coupled Receptor L3 (ADGRL3) is strongly linked to several EDs, and loss-of-function models have shown the impacts of this gene on several core ED-related behaviors. For example, adgrl3.1<sup>-/-</sup> zebrafish show high levels of hyperactivity. However, our understanding of the mechanisms by which this gene influences behavior ...[more]

PMID: 37783687

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Project description:BackgroundFOXP1 syndrome is a genetic neurodevelopmental disorder associated with complex clinical presentations including global developmental delay, mild to profound intellectual disability, speech and language impairment, autism traits, attention-deficit/hyperactivity disorder (ADHD), and a range of behavioral challenges. To date, much of the literature focuses on childhood symptoms and little is known about the FOXP1 syndrome phenotype in adolescence or adulthood.MethodsA series of caregiver interviews and standardized questionnaires assessed psychiatric and behavioral features of 20 adolescents and adults with FOXP1 syndrome. Clinical interviews captured change in various psychiatric manifestations over time. Medication, social, educational, and vocational history was collected, and visual analog scales measured top caregiver concerns during childhood and adolescence/adulthood.ResultsAnxiety and externalizing behaviors were common in this cohort and psychiatric features, such as psychosis or bipolar symptoms, were present in two participants. There was no reported regression or loss of skills, early in development or during adolescence/adulthood. Medication use was common particularly for features of ADHD, although multiple trials were required for some individuals to achieve benefit. Standardized assessments accurately picked up on externalizing symptoms and were less sensitive to internalizing symptoms. Educational setting varied up until late elementary school and gradually shifted to special education. Cognitive and developmental concerns were reported as primary during childhood and independence/safety and housing concerns became top concerns by adolescence/adulthood. Caregivers reported continued development in adaptive skills even into adulthood.ConclusionsTaken together, results are reassuring, with many families reporting their adolescent and adult children continued to gain skills over time, particularly related to increased independence in communication and personal care. There were no reports of developmental regression, neuropsychiatric decompensation or catatonia.

Dataset Information

Adgrl3.1-deficient zebrafish show noradrenaline-mediated externalizing behaviors, and altered expression of externalizing disorder-candidate genes, suggesting functional targets for treatment.

Publications

adgrl3.1-deficient zebrafish show noradrenaline-mediated externalizing behaviors, and altered expression of externalizing disorder-candidate genes, suggesting functional targets for treatment.

Similar Datasets

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