Motor Impairments Correlate with Social Deficits and Restricted Neuronal Loss in an Environmental Model of Autism

摘要

Background Motor impairments are amongst the earliest and most consistent signs of autism spectrum disorders but are not used as diagnostic criteria. In addition, the relationship between motor and cognitive impairments and their respective neural substrates remain unknown. Methods Here, we aimed at determining whether a well-acknowledged animal model of autism spectrum disorders, the valproic acid model, displays motor impairments and whether they may correlate with social deficits and neuronal loss within motor brain areas. For this, pregnant female mice (C57BL/6J) received valproic acid (450 mg/kg) at embryonic day 12.5 and offspring underwent a battery of behavioral analyses before being killed for histological correlates in motor cortex, nigrostriatal pathway, and cerebellum. Results We show that while valproic acid male mice show both social and motor impairments, female mice only show motor impairments. Prenatal valproic acid exposure induces specific cell loss within the motor cortex and cerebellum and that is of higher magnitude in males than in females. Finally, we demonstrate that motor dysfunction correlates with reduced social behavior and that motor and social deficits both correlate with a loss of Purkinje cells within the Crus I cerebellar area. Conclusions Our results suggest that motor dysfunction could contribute to social and communication deficits in autism spectrum disorders and that motor and social deficits may share common neuronal substrates in the cerebellum. A systematic assessment of motor function in autism spectrum disorders may potentially help the quantitative diagnosis of autism spectrum disorders and strategies aimed at improving motor behavior may provide a global therapeutic benefit. valproic acid , cerebellum , motor cortex , gait , Purkinje cells Significance Statement The paper’s main message is that motor impairments in ASD may be indicative of this pathology and may even underlie some of its core cognitive and behavioral features. For this, we conducted a detailed analysis of motor and social behavior in both sexes of a VPA mouse model and correlated these findings to cell loss in specific brain areas such as the cerebellum and motor cortex. Our work brings evidence that motor behavior can be used as a quantitative approach for the diagnosis of ASD and is indicative of social deficits. This opens new avenues in the diagnosis and treatment of ASD targeting the affected brain areas.