Abnormal Cerebellar Development in Autism Spectrum Disorders

Abstract

Autism spectrum disorders (ASD) comprise a group of heterogeneous neurodevelopmental conditions characterized by impaired social interactions and repetitive behaviors with symptom onset in early infancy. The genetic risks for ASD have long been appreciated: concordance of ASD diagnosis may be as high as 90% for monozygotic twins and 30% for dizygotic twins, and hundreds of mutations in single genes have been associated with ASD. Nevertheless, only 5–30% of ASD cases can be explained by a known genetic cause, suggesting that genetics is not the only factor at play. More recently, several studies reported that up to 40% of infants with cerebellar hemorrhages and lesions are diagnosed with ASD. These hemorrhages are overrepresented in severely premature infants, who are born during a period of highly dynamic cerebellar development that encompasses an approximately 5-fold size expansion, an increase in structural complexity, and remarkable rearrangements of local neural circuits. The incidence of ASD-causing cerebellar hemorrhages during this window supports the hypothesis that abnormal cerebellar development may be a primary risk factor for ASD. However, the links between developmental deficits in the cerebellum and the neurological dysfunctions underlying ASD are not completely understood. Here, we discuss key processes in cerebellar development, what happens to the cerebellar circuit when development is interrupted, and how impaired cerebellar function leads to social and cognitive impairments. We explore a central question: Is cerebellar development important for the generation of the social and cognitive brain or is the cerebellum part of the social and cognitive brain itself?

The GM2 gangliosidoses: Unlocking the mysteries of pathogenesis and treatment

“…The turnover and remodeling of dendritic spines of Purkinje cells is an important aspect of neuronal plasticity required for development, learning and adaptation [ 116 , 117 ]. These processes have been widely implicated in disorders such as autism [ 118 , 119 ] and psychiatric illness [ 120 , 121 ]. Dendritic sprouting, pruning and membrane maintenance are metabolically expensive as demonstrated by the effects caused by dysfunctional mitochondrial fission and migration onto dendritic arborizations of Purkinje cells and the role of accumulating reactive oxygen species contributes to cerebellar degeneration [ 122 ].…”

Deficiency of the ywhaz gene, involved in neurodevelopmental disorders, alters brain activity and behaviour in zebrafish

“…Indeed, the important function of Ywhaz in neurogenesis and neuronal differentiation was previously demonstrated in mice KO models [1][2][3][4][5], and disrupted neurogenesis is a known risk factor for neurodevelopmental disorders [33]. Although expressed pan-neuronally, ywhaz presents a stronger expression in larvae cerebellum, a brain region whose dysfunction has been related to neurodevelopmental disorders [34,35]. Interestingly, a decreased YWHAZ expression was reported in the cerebellum of ASD patients [6].…”

White matter microstructural and morphometric alterations in autism: Implications for intellectual capabilities

“…The left-side Crus I/II supports the socioemotional inferences and motion-related imitation (Arnold Anteraper et al, 2019, Jack andPelphrey, 2015), whereas the right counterpart subserves the complex socio-emotional reasoning and sensorimotor integration (D'Mello and Stoodley, 2015, Siciliano andClausi, 2020) in neurotypical people. The GM morphometry and function of Crus I/II are reported to be involved in impaired socioemotional (Siciliano and Clausi, 2020) and language processes, alongside repetitive behaviors (D'Mello and in people (van der Heijden et al, 2021) and mice models (Kelly et al, 2020, Stoodley et al, 2017 with ASD. Intellectually able youth with ASD also have specific developmental changes in GM morphometry at these loci (Lin et al, 2015, Siciliano andClausi, 2020).…”