Patient-Specific Neurons Reveal Vital Clues About Autism

The brains of some people with autism spectrum disorder grow faster than usual early on in life, often before diagnosis. Now new research from scientists at the Salk Institute has used cutting-edge stem cell-based techniques to elucidate those mechanisms that drive excess brain growth, which affects as many as 30 percent of people with autism.

These findings show that it is possible to use stem cell reprogramming technologies to model the earliest stages of complex disorders and to evaluate potential therapeutic drugs. The Salk team, led by Alysson Muotri, discovered that stem cell-derived neurons, derived from stem cells that had been made from cells taken from autism patients, made fewer connections in culture compared to cells from healthy individuals. These same scientists also restored cell-cell communication between these cells by adding a growth factor called IGF-1 (insulin-like growth factor-1). IGF-1 is in the process of being evaluated in clinical trials of autism.

“This technology allows us to generate views of neuron development that have historically been intractable,” said senior investigator Fred H. Gage. “We’re excited by the possibility of using stem cell methods to unravel the biology of autism and to possibly screen for new drug treatments for this debilitating disorder.”

In the United States alone, autism affects approximately one out of every 68 children. Autistic children have problems communicating, show an inhibited ability to interact with others, and usually engage in repetitive behaviors. Mind you, the symptomatic manifestations in autistic children can vary dramatically in type and severity. Autism, to date, has no known, identified cause.

In 2010, Gage and collaborators recreated features of Rett syndrome (a rare disorder that shares features of autism but is caused by mutations in a single gene; MECP2) in a cell culture system. They extracted skin cells from Rett Syndrome patients and converted those cells into induced pluripotent stem cells (iPSCs). Then Gage and others differentiated those Rett-Syndrome-specific iPSCs into neurons, which they grew in culture. These neurons were then studied in detail in a neuron-specific culture system. “In that study, induced pluripotent stem cells gave us a window into the birth of a neuron that we would not otherwise have,” said Marchetto, the study’s first author. “Seeing features of Rett syndrome in a dish gave us the confidence to next study classical autism.”

In this new study, Gage and others created iPSCs from autism patients whose brains had grown up to 23 percent faster than usual during toddlerhood but had subsequently normalized. These iPSCs were then differentiated into neuron precursor cells (NPCs). Examinations of these NPCs revealed that the NPCs made from iPSCs derived from autism patients proliferated faster than those derived from typically developing individuals. This finding supports a theory advanced by some experts that brain enlargement is caused by disruptions to the cell’s normal cycle of division, according to Marchetto.

In addition, the neurons derived from autism-specific iPSCs behaved abnormally in culture. They fired less often compared with those cells derived from healthy people. The activity of these neurons, however, improved if they were treated with IGF-1. IGF-1 enhances the formation of cell-cell connections between neurons, and the establishment and stabilization of these connections seem to normalize neuronal function.

Muotri and Gage and others plan to use these patient-derived cells to elucidate the molecular mechanisms behind IGF-1’s effects. They will examine changes in gene expression and attempt to correlate them with changes in neuronal function. Although the newly derived cells are far from the patients’ brains, a brain cell by itself may, hopefully, reveal important clues about a person and their brain.

This work was published in the journal Molecular Psychiatry: M. C. Marchetto et al., “Altered proliferation and networks in neural cells derived from idiopathic autistic individuals,” Molecular Psychiatry, 2016; DOI: 10.1038/mp.2016.95.


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Professor of Biochemistry at Spring Arbor University (SAU) in Spring Arbor, MI. Have been at SAU since 1999. Author of The Stem Cell Epistles. Before that I was a postdoctoral research fellow at the University of Pennsylvania in Philadelphia, PA (1997-1999), and Sussex University, Falmer, UK (1994-1997). I studied Cell and Developmental Biology at UC Irvine (PhD 1994), and Microbiology at UC Davis (MA 1986, BS 1984).