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Prog Neurobiol. 2015 Jul;130:1-28. doi: 10.1016/j.pneurobio.2015.03.004. Epub 2015 Apr 9.

Modeling a model: Mouse genetics, 22q11.2 Deletion Syndrome, and disorders of cortical circuit development.

Author information

1
Institute for Neuroscience, Department of Pharmacology & Physiology, The George Washington University, Washington, DC, United States.
2
Department of Neurobiology and Anatomy, Neuroscience Graduate Program, and Center for Neuroscience, West Virginia University School of Medicine, Morgantown, West Virginia.
3
Institute for Neuroscience, Department of Pharmacology & Physiology, The George Washington University, Washington, DC, United States; Department of Psychology, The George Washington University, Washington, DC, United States.
4
Institute for Neuroscience, Department of Pharmacology & Physiology, The George Washington University, Washington, DC, United States. Electronic address: lamantia@gwu.edu.

Abstract

Understanding the developmental etiology of autistic spectrum disorders, attention deficit/hyperactivity disorder and schizophrenia remains a major challenge for establishing new diagnostic and therapeutic approaches to these common, difficult-to-treat diseases that compromise neural circuits in the cerebral cortex. One aspect of this challenge is the breadth and overlap of ASD, ADHD, and SCZ deficits; another is the complexity of mutations associated with each, and a third is the difficulty of analyzing disrupted development in at-risk or affected human fetuses. The identification of distinct genetic syndromes that include behavioral deficits similar to those in ASD, ADHC and SCZ provides a critical starting point for meeting this challenge. We summarize clinical and behavioral impairments in children and adults with one such genetic syndrome, the 22q11.2 Deletion Syndrome, routinely called 22q11DS, caused by micro-deletions of between 1.5 and 3.0 MB on human chromosome 22. Among many syndromic features, including cardiovascular and craniofacial anomalies, 22q11DS patients have a high incidence of brain structural, functional, and behavioral deficits that reflect cerebral cortical dysfunction and fall within the spectrum that defines ASD, ADHD, and SCZ. We show that developmental pathogenesis underlying this apparent genetic "model" syndrome in patients can be defined and analyzed mechanistically using genomically accurate mouse models of the deletion that causes 22q11DS. We conclude that "modeling a model", in this case 22q11DS as a model for idiopathic ASD, ADHD and SCZ, as well as other behavioral disorders like anxiety frequently seen in 22q11DS patients, in genetically engineered mice provides a foundation for understanding the causes and improving diagnosis and therapy for these disorders of cortical circuit development.

KEYWORDS:

ADHD; Animal models; Autism; Cortex; Schizophrenia

PMID:
25866365
PMCID:
PMC5019355
DOI:
10.1016/j.pneurobio.2015.03.004
[Indexed for MEDLINE]
Free PMC Article

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