Abnormal Cerebellar Physiology and Development in the Autistic Brain

University Of Chicago, Chicago IL

Investigators

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Abstract

PROJECT SUMMARY / ABSTRACT Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder, characterized by deficits in social interaction and increased repetitive behaviors. Additional motor abnormalities have implicated the cerebellum in autistic pathology [8]. Recently, impaired synaptic pruning across the brain has been observed in post- mortem tissue from autistic patients and also in mouse models of ASD [24]. Our laboratory recently reported impaired synaptic pruning in the cerebellum by revealing delays in the competitive elimination of surplus climbing fibers [22]. To further investigate cerebellar abnormalities in ASD, I am studying climbing fiber (CF) ? Purkinje cell synaptic transmission in the 15q11-13 mouse model of ASD [see ref. #21 for description of mouse model]. Specifically, I will determine if Ube3a, a gene within the 15q11-13 region, is involved in the autistic-like phenotype in 15q11-13 mice. Ube3a has been associated with autistic-like behaviors in a dosage-dependent manner [23]. I propose to search for connections between altered Ube3a levels and aberrant CF-Purkinje cell physiology. Additionally, we plan to explore the effect of Ube3a alone on cerebellar physiology in a separate ASD mouse model that selectively overexpresses Ube3a in Purkinje cells. One major training goal of this proposal is for me to learn calcium imaging so I can answer questions about calcium flow in Purkinje cell spines, fine dendritic branches, and primary dendritic branches in the 15q11-13 and Ube3a OE mouse models of ASD. Our findings from the proposed project will highlight cerebellar physiological abnormalities that may contribute to aberrant synaptic transmission in a mouse model of ASD, and also explore the regulation of a candidate gene that is associated with the autistic-like phenotype. Pathological synaptic development and function is common to many different brain disorders, such as ASD, and our findings from this study will provide important insight into the pathology of other such disorders.