31723
Translational Assessments in Two Genetic Preclinical Models of Disrupted Chromatin Processes: Development and Motor Outcomes

Poster Presentation
Friday, May 3, 2019: 11:30 AM-1:30 PM
Room: 710 (Palais des congres de Montreal)
S. Petkova1, C. P. Canales2, A. S. Nord3, J. Ellegood4, J. P. Lerch4 and J. L. Silverman5, (1)MIND Institute and Department of Psychiatry and Behavioral Sciences, Sacramento, CA, (2)Center for Neuroscience | MIND Institute, Department of Psychiatry and Behavioral Sciences, University of California Davis, Davis, CA, (3)Center for Neuroscience, Department of Neurobiology, Physiology, & Behavior, University of California, Davis, Davis, CA, (4)Mouse Imaging Centre, Hospital for Sick Children, Toronto, ON, Canada, (5)MIND Institute and Department of Psychiatry and Behavioral Sciences, University of California Davis School of Medicine, Sacramento, CA
Background:

Numerous genes related to chromatin modification processes are among the top autism -associated risk genes, including AT-Interactive Domain 1B (ARID1B) and Chromodomain-Helicase DNA Binding Protein 8 (CHD8) (Cook & Scherer, 2008, O’Roak & State, 2008, O Roak 2014, Lossifov 2014, Werling 2018). These two candidate genes have related functional activities albeit act via differential pathways: ARID1B is a SWI/SNF complex protein in neuronal BAF chromatin complexes, and CHD8 encodes an ATP-dependent chromatin helicase.

Objectives:

To examine developmental outcomes such as physical growth and neurological reflexes in two preclinical models of genetically defined ASD.

To focus on motor as a key domain because: a) there is a strong correlation between motor and social communication, b) there is a strong correlation between motor skills and assessment of cognitive abilities, and c) motor is highly translatable between preclinical models and human studies.

Methods:

Heterozygous Arid1b+/- generated by the Toronto Centre for Phenogenomics, Chd8+/del5 from the Nord laboratory (Gompers et al., 2017) and wildtype littermate, sex and age matched controls were assayed in developmental milestones on postnatal days (PND) 2-14, similar to those previously described (Fox, 1965) with extended detail. Physical measurements such as body weight, length, and head width were measured. Progress of motor reflexes such as negative geotaxis, cliff avoidance, righting reflex and circle transverse assayed for neonatal hypotonia and ataxia. Milestones for tracking development of fore and hind limb strength were forelimb grasp, forelimb bar holding, forelimb and hindlimb hang tests. Adult gross and fine motor abilities including balance, strength, coordination, locomotive activity, and gait were evaluated using classic tests such as the open field, rotarod and innovative gait mapping using the treadmill scanning DigiGaitTM system.

Results:

Arid1b+/- pups were impaired on several parameters of developmental milestones compared to littermate Arid1b+/+ controls. Body weight, length and head width were smaller in Arid1b+/-, indicating atypical growth and development. Longer latencies to reverse from an inclined position in negative geotaxis and to traverse out of circle were detected in Arid1b+/-, highlighting delayed motor-related neurological reflexes and the onset of walking. Adult Arid1b+/- were also impaired on multiple parameters of locomotive activity. In contrast, Chd8+/del5 showed no substantial delays nor deficits in growth, motor skill development or strength during neonatal testing, compared to wildtype littermates. Adult Chd8+/del5 also exhibited few gait abnormalities.

Conclusions:

Many neurodevelopmental disorders ranging from the broadly defined ASD to the rare genetic syndromes have common features of developmental delay and motor dysfunction. An emphasis on finely detailed motor skill analyses across development as outcome measures has been understudied. Broadly, CHD8 and ARID1B function as chromatin modification proteins. Herein, we described developmental delays and numerous motor outcomes using finely tuned clinically-relevant assays in genetic preclinical models of these two ASD risk genes. Investigation of motor outcomes is essential for demonstrating the test the utility of innovative drug designs and validate other traditional medicinal therapies that may be in the drug discovery pipeline.

See more of: Animal Models
See more of: Animal Models