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

Abstract

BackgroundMotor 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.MethodsHere, 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.ResultsWe 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.ConclusionsOur 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.

Shared developmental gait disruptions across two mouse models of neurodevelopmental disorders

“…The Mecp2 mouse model of Rett Syndrome displayed a reduced stride length in adulthood (Vogel Ciernia et al, 2017), one of the gait metrics we observed to be perturbed in both CD and Nf1 +/R681X models. Similarly, the valproic acid mouse model of ASD has previously been reported to exhibit a decreased stride length in the juvenile period compared to controls (Al Sagheer et al, 2018). Although this direction of effect is opposite the increased stride length we observed in both CD and Nf1 +/R681X developing mice, a correction for body length, such as we performed, might reveal greater similarity across models.…”

A Systematic Review of the Valproic-Acid-Induced Rodent Model of Autism

“…The sex of the rodents influences behavioural outcomes in studies that consisted of both males and females. VPA exposure appeared to have no effect or a lesser effect in females [36][37][38][39][40], indicating females possess some resistance to social impairment induced by VPA, as opposed to males [41].…”

Aging with Autism Departs Greatly from Typical Aging

“…Yet, for well over two decades now, basic science has provided objective, physical quantification of neurological problems in ASD that supports an earlier neurological model [46,47] amenable to explain many of the social and communication issues defining the condition. Patterns of cerebellar dysfunction [48,49], motor and vestibular coordination [44] and sensory-motor integration issues [2] have been reproduced across tractable biorhythms using non-invasive means [50][51][52][53][54][55][56]. Perhaps these data can help us derive further criteria to stratify ASD and help design treatments tailored to address the phenotypic features that each subgroup may reveal.…”