Developmental and Behavioral Phenotypes in a Mouse Model of DDX3X Syndrome

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Biol Psychiatry. 2021 Jun 7;S0006-3223(21)01363-9. doi: 10.1016/j.biopsych.2021.05.027.

Developmental and Behavioral Phenotypes in a Mouse Model of DDX3X Syndrome

Andrea Boitnott, Marta Garcia-Forn, Dévina C Ung, Kristi Niblo, Danielle Mendonca, Yeaji Park, Michael Flores, Sylvia Maxwell, Jacob Ellegood, Lily R Qiu, Dorothy E Grice, Jason P Lerch, Mladen-Roko Rasin, Joseph D Buxbaum, Elodie Drapeau, Silvia De Rubeis

Icahn School of Medicine at Mount Sinai, New York, New York. New York University, College of Arts and Sciences, New York, New York. The Bronx High School of Science, New York, New York. Mouse Imaging Centre, Hospital for Sick Children, Toronto, Ontario, Canada. Wellcome Centre for Integrative Neuroimaging, FMRIB, Nuffield Department of Clinical Neuroscience, University of Oxford, Oxford, United Kingdom. University of Toronto, Toronto, Ontario, Canada Rutgers University, Robert Wood Johnson Medical School, Piscataway, New Jersey.

Service type: Knockout mice


Background: Mutations in the X-linked gene DDX3X account for approximately 2% of intellectual disability in females, often comorbid with behavioral problems, motor deficits, and brain malformations. DDX3X encodes an RNA helicase with emerging functions in corticogenesis and synaptogenesis. Methods: We generated a Ddx3x haploinsufficient mouse (Ddx3x+/- females) with construct validity for DDX3X loss-of-function mutations. We used standardized batteries to assess developmental milestones and adult behaviors, as well as magnetic resonance imaging and immunostaining of cortical projection neurons to capture early postnatal changes in brain development. Results: Ddx3x+/- females showed physical, sensory, and motor delays that evolved into behavioral anomalies in adulthood, including hyperactivity, anxiety-like behaviors, cognitive impairments in specific tasks (e.g., contextual fear memory but not novel object recognition memory), and motor deficits. Motor function declined with age but not if mice were previously exposed to behavioral training. Developmental and behavioral changes were associated with a reduction in brain volume, with some regions (e.g., cortex and amygdala) disproportionally affected. Cortical thinning was accompanied by defective cortical lamination, indicating that Ddx3x regulates the balance of glutamatergic neurons in the developing cortex. Conclusions: These data shed new light on the developmental mechanisms driving DDX3X syndrome and support construct and face validity of this novel preclinical mouse model. Keywords: Corticogenesis; DDX3X syndrome; Intellectual disability; Movement disorder; Neurodevelopment.

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