Prioritizing the development of mouse models for childhood brain disorders

• Published in: Neuropharmacology 2016-01, Vol.100, p.2-16
• Main Authors: Ogden, Kevin K., Ozkan, Emin D., Rumbaugh, Gavin
• Format: Article
• Language: English
• Subjects: Animals; Autism; Brain Diseases - genetics; Development; Disease Models, Animal; Epilepsy; Humans; Intellectual disability; Mice; Mice, Knockout; Mouse model; Mutation; Neurodevelopmental Disorders - genetics; Phenotype; Research Design; Risk Factors; Schizophrenia; Synapse; Synapses - genetics; Syngap1
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2015.07.029

Mutations in hundreds of genes contribute to cognitive and behavioral dysfunction associated with developmental brain disorders (DBDs). Due to the sheer number of risk factors available for study combined with the cost of developing new animal models, it remains an open question how genes should be prioritized for in-depth neurobiological investigations. Recent reviews have argued that priority should be given to frequently mutated genes commonly found in sporadic DBD patients. Intrigued by this idea, we explored to what extent “high priority” risk factors have been studied in animals in an effort to assess their potential for generating valuable preclinical models capable of advancing the neurobiological understanding of DBDs. We found that in-depth whole animal studies are lacking for many high priority genes, with relatively few neurobiological studies performed in construct valid animal models aimed at understanding the pathological substrates associated with disease phenotypes. However, some high priority risk factors have been extensively studied in animal models and they have generated novel insights into DBD patho-neurobiology while also advancing early pre-clinical therapeutic treatment strategies. We suggest that prioritizing model development toward genes frequently mutated in non-specific DBD populations will accelerate the understanding of DBD patho-neurobiology and drive novel therapeutic strategies. This article is part of the Special Issue entitled ‘Synaptopathy – from Biology to Therapy’. •Over 500 genetic risk factors for developmental brain disorders (DBDs) exist.•Too few risk factors have been studied in-depth using mouse models.•Resource constraints require prioritizing genes for in-depth study.•We made a list of high priority genes that can serve as a new generation of models.•Successes from this list suggest modeling these genes will advance the DBD field.