Integrated approach to the neurobiology of autism spectrum disorders

Flora Vaccarino, M.D.
Yale University

Autism spectrum disorders are thought to arise from various genetic alterations that cause abnormal brain and nervous system development. To better understand the role these alterations play in the development of neurons, Flora Vaccarino, of Yale University, and her colleagues will take advantage of a recently developed technique for generating stem cells from skin biopsy samples. The technique reprograms skin cells into so-called induced pluripotent stem (iPS) cells, which can then differentiate into any of the body’s cell types, including neural stem cells. Vaccarino’s team will obtain skin samples from participants in the Simons Simplex Collection, a cohort of families with one child with autism and unaffected parents.

The researchers will derive iPS cell lines from people with autism and controls and induce the cells to differentiate into neuronal stem cells. Then, they will examine the cells for various phenotypic characteristics — such as morphology, surface marker expression and mRNA expression — as they proliferate, differentiate into neuronal progenitor cells, mature into neurons, and form connections with other neurons. The researchers will also use high-resolution techniques to look for changes in DNA as the neural stem cells differentiate, including variations in copy-number and DNA methylation.

Vaccarino says her team’s stem cell studies will allow them to recapitulate the biological steps involved in the development of neurons, and observe how this process might be altered by autism-linked genetic variants. The study also aims to establish the validity of iPS cells as a tool for autism research by demonstrating that they can reproducibly give rise to brain neurons while maintaining the unique genetic traits of the people from whom they originate.