Abstract
While cerebellar alterations may play a crucial role in the development of core autism spectrum disorder (ASD) symptoms, their pathophysiology on the function of cerebrocerebellar circuit loops is largely unknown. We combined multimodal MRI (9.4 T) brain assessment of the prenatal rat valproate (VPA) model and correlated immunohistological analysis of the cerebellar Purkinje cell number to address this question. We hypothesized that a suitable functional MRI (fMRI) paradigm might show some altered activity related to disrupted cerebrocerebellar information processing. Two doses of maternal VPA (400 and 600 mg/kg, s.c.) were used. The higher VPA dose induced 3% smaller whole brain volume, the lower dose induced 2% smaller whole brain volume and additionally a focal gray matter density decrease in the cerebellum and brainstem. Increased cortical BOLD responses to whisker stimulation were detected in both VPA groups, but it was more pronounced and extended to cerebellar regions in the 400 mg/kg VPA group. Immunohistological analysis revealed a decreased number of Purkinje cells in both VPA groups. In a detailed analysis, we revealed that the Purkinje cell number interacts with the cerebral BOLD response distinctively in the two VPA groups that highlights atypical function of the cerebrocerebellar circuit loops with potential translational value as an ASD biomarker.
Highlights
While cerebellar alterations may play a crucial role in the development of core autism spectrum disorder (ASD) symptoms, their pathophysiology on the function of cerebrocerebellar circuit loops is largely unknown
Despite these seminal findings highlighting the potential functional impact of disrupted cerebrocerebellar loops in ASD8,22, fundamental questions about the pathophysiology of these cerebrocerebellar loops have remained unanswered. Their translational utility is unknown, limiting the progress in pursuing objective neuroimaging biomarkers in ASD. We addressed these questions by combining multimodal neuroimaging and correlated immunohistological analysis of the cerebellar Purkinje cell number in a prenatal rat valproate (VPA) model
Anatomical scans at measurement 1 revealed that prenatal exposure to VPA resulted in 3.2% smaller whole brain volume in the VPA600 group (p = 0.006, effect size: −81.1 mm3) compared to controls
Summary
While cerebellar alterations may play a crucial role in the development of core autism spectrum disorder (ASD) symptoms, their pathophysiology on the function of cerebrocerebellar circuit loops is largely unknown. We revealed that the Purkinje cell number interacts with the cerebral BOLD response distinctively in the two VPA groups that highlights atypical function of the cerebrocerebellar circuit loops with potential translational value as an ASD biomarker. There is recent mechanistic evidence in mice showing that in juvenile life the chemogenetic perturbation of the activity of posterior vermal cerebellar regions modulates the expression of ASD-related behaviors in adulthood[21]. Despite these seminal findings highlighting the potential functional impact of disrupted cerebrocerebellar loops in ASD8,22, fundamental questions about the pathophysiology of these cerebrocerebellar loops have remained unanswered. Their translational utility is unknown, limiting the progress in pursuing objective neuroimaging biomarkers in ASD
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