Alterations in Cerebellar Microtubule Cytoskeletal Network in a ValproicAcid-Induced Rat Model of Autism Spectrum Disorders

Autism spectrum disorders (ASD) are neurodevelopmental diseases characterised by deficits in social communication, restricted interests, and repetitive behaviours. The growing body of evidence points to a role for cerebellar changes in ASD pathology. Some of the findings suggest that not only motor problems but also social deficits, repetitive behaviours, and mental inflexibility associated with ASD are connected with damage to the cerebellum. However, the understanding of this brain structure's functions in ASD pathology needs future investigations. Therefore, in this study, we generated a rodent model of ASD through a single prenatal administration of valproic acid (VPA) into pregnant rats, followed by cerebellar morphological studies of the offspring, focusing on the alterations of key cytoskeletal elements. The expression (Western blot) of alpha/beta-tubulin and the major neuronal MT-associated proteins (MAP) such as MAP-Tau and MAP1B, MAP2, MAP6 (STOP) along with actin-crosslinking alpha II-spectrin and neurofilament light polypeptide (NF-L) was investigated. We found that maternal exposure to VPA induces a significant decrease in the protein levels of alpha/beta-tubulin, MAP-Tau, MAP1B, MAP2, and alpha II-spectrin. Moreover, excessive MAP-Tau phosphorylation at (Ser396) along with key Tau-kinases activation was indicated. Immunohistochemical staining showed chromatolysis in the cerebellum of autistic-like rats and loss of Purkinje cells shedding light on one of the possible molecular mechanisms underpinning neuroplasticity alterations in the ASD brain.

Automated summary

In this study, a rodent model of ASD was induced through prenatal exposure to valproic acid (VPA), and the researchers found that maternal VPA exposure led to significant decreases in the levels of key cytoskeletal elements, as well as excessive phosphorylation of MAP-Tau and activation of Tau kinases. Immunohistochemical staining revealed chromatolysis and loss of Purkinje cells in the cerebellum, suggesting potential molecular mechanisms underlying neuroplasticity alterations in the ASD brain.