Compelling evidence suggests that the 15q11-13 chromosomal region is likely to play a role in autism pathogenesis. Mutations of the UBE3A gene, which is located in this region, cause Angelman syndrome (AS), a neurodevelopmental disorder that has strong phenotypic overlap with autism. UBE3A is an E3 ubiquitin ligase and has been shown to be an important regulator of protein homeostasis and synapse development and plasticity. Separately, there is growing evidence that neuronal autophagy plays a role in supporting proper morphological development and synaptic connectivity refinement.
Shenfeng Qiu and his colleagues at the University of Arizona hypothesize that the synaptogenesis and pruning deficits in AS mice may result from reductions in neuronal autophagy and impaired protein metabolism. To assess this, Qiu and his team will determine whether the synapse defects in AS can be rescued by enhancing neuronal autophagy function. The team has found evidence of impaired synaptogenesis, temporal alterations of synapse maturations, and defective synapse pruning during an early developmental period in a mouse model of AS with a maternally inherited UBE3A mutant allele.
Qiu’s team will create a novel transgenic mouse line in which enhanced neuronal autophagy can be temporally controlled in the excitatory cortical projections neurons, and turned on during a critical period of synapse pruning and circuit refinement. They will investigate the effects of the transgene on neuronal morphology (dendritic structure, spine density and morphology) and function (synapse developmental maturation and local circuit organization). The researchers hypothesize that enhanced neuronal autophagy will, to certain extent, rescue the synaptic and circuit deficits seen in the AS mouse model. Given the strong phenotypic overlap between AS and autism, any rescue of synaptic deficits in this AS mouse model would support further assessment of the importance of dysregulated autophagy in autism as well.
Interagency Autism Coordinating Committee (IACC)
Autism Research Database (AFD)
