Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder, characterized by deficits in socialinteraction and increased repetitive behaviors. Additional motor abnormalities have implicated the cerebellumin 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 reportedimpaired synaptic pruning in the cerebellum by revealing delays in the competitive elimination of surplusclimbing 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 mousemodel]. Specifically, I will determine if Ube3a, a gene within the 15q11-13 region, is involved in the autistic-likephenotype in 15q11-13 mice. Ube3a has been associated with autistic-like behaviors in a dosage-dependentmanner [23]. I propose to search for connections between altered Ube3a levels and aberrant CF-Purkinje cellphysiology. Additionally, we plan to explore the effect of Ube3a alone on cerebellar physiology in a separateASD mouse model that selectively overexpresses Ube3a in Purkinje cells. One major training goal of thisproposal is for me to learn calcium imaging so I can answer questions about calcium flow in Purkinje cellspines, fine dendritic branches, and primary dendritic branches in the 15q11-13 and Ube3a OE mouse modelsof ASD. Our findings from the proposed project will highlight cerebellar physiological abnormalities that maycontribute to aberrant synaptic transmission in a mouse model of ASD, and also explore the regulation of acandidate gene that is associated with the autistic-like phenotype. Pathological synaptic development andfunction is common to many different brain disorders, such as ASD, and our findings from this study willprovide important insight into the pathology of other such disorders.
Interagency Autism Coordinating Committee (IACC)
Autism Research Database (AFD)
