Abstract
Autistic spectral disorder (ASD) is a prevalent neurodevelopmental disease that affects multiple brain regions. Both clinical and animal studies have revealed the possible involvement of the cerebellum in ASD pathology. In this study, we generated a rodent ASD model through a single prenatal administration of valproic acid (VPA) into pregnant mice, followed by cerebellar morphological and functional studies of the offspring. Behavioral studies showed that VPA exposure led to retardation of critical motor reflexes in juveniles and impaired learning in a tone-conditioned complex motor task in adults. These behavioral phenotypes were associated with premature migration and excess apoptosis of the granular cell (GC) precursor in the cerebellar cortex during the early postnatal period, and the decreased cell density and impaired dendritic arborization of the Purkinje neurons. On acute cerebellar slices, suppressed synaptic transmission of the Purkinje cells were reported in the VPA-treated mice. In summary, converging evidence from anatomical, electrophysiological and behavioral abnormalities in the VPA-treated mice suggest cerebellar pathology in ASD and indicate the potential values of motor dysfunction in the early diagnosis of ASD.
Highlights
The cerebellum has been recognized as the brain region mediating fine motor coordination and complex motor skill learning
As no significant difference was found in the learning ability on the Rota-rod (two-way analysis of variance (ANOVA) with repeated measures, interaction effect, F(5,120) = 0.9056, P = 0.4799, Supplementary Figure 1A), more sensitive motor learning paradigms were expected
The valproic acid (VPA)-treated group showed a sharp increase in duration on the walkway, which was maintained at relatively low levels in the control group (two-way ANOVA, treatment × training day effect: F(7,1496) = 2.54, P = 0.0134; Bonferroni post hoc comparison between VPA- and salinetreated group: P = 0.0137, 0.0479 and 0.0371 from day 6 to day 8; Figure 1B)
Summary
The cerebellum has been recognized as the brain region mediating fine motor coordination and complex motor skill learning. Recent evidence has revealed the role of the cerebellum in psychiatric disorders including major depressive disorder (Su et al, 2014), schizophrenia (Mothersill et al, 2016) and autistic spectral disorder (ASD; Fatemi et al, 2012; Wang et al, 2014). Postmortem examinations of ASD patient brains reported cerebellar neuropathology (Hampson and Blatt, 2015). ASD children frequently present cerebellar associated motor disorders (McPhillips et al, 2014; Mosconi et al, 2015), which can occur at early age before the onset of language or social deficits (Lloyd et al, 2013). The potential value of motor dysfunction in the early diagnosis of ASD is being continuously discussed (Whyatt and Craig, 2013; Zwaigenbaum et al, 2013). It is necessary to further elaborate the cerebellar neuropathology associated with ASD
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