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Neurons made from people with autism show distinct markers

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Virginia Hughes
12 November 2013

Quiet storms: Neurons derived from stem cells of children with autism (right) show more markers of inhibitory signaling (pink and green) than unaffected controls (left) do.

Researchers have created neurons from the skin cells of children with autism, according to an unpublished study presented Monday at the 2013 Society for Neuroscience annual meeting in San Diego. These neurons show several distinct features, including elevated markers of inhibitory signaling compared with controls.

Over the past few years, researchers have made so-called induced pluripotent stem (iPS) cells by reprogramming skin cells taken from individuals with several autism-related disorders, including Timothy syndrome, Rett syndrome and fragile X syndrome. Using certain chemical concoctions, these cells can be coaxed into becoming neurons.

The new study made neurons in this way from four children with idiopathic, or unexplained, autism and their unaffected family members. All of the children with autism also have abnormally large heads, a common feature of the disorder.

Neurons made from children with autism show a shorter cell cycle than controls do, indicating that they proliferate more quickly, the researchers found.

This makes sense, notes Jessica Mariani, a postdoctoral associate in Flora Vaccarino^’s lab at the Yale Child Study Center who presented the work. “It’s saying maybe they have a big brain because they are proliferating much more.”

The autism neurons also have shorter dendrites, neuronal projections that receive electrical signals, and less branching, compared with controls. “They seem to be less complex,” Mariani says.

The researchers also performed RNA sequencing to investigate gene expression in the cells. Neurons derived from children with autism show increased expression of genes that mark inhibitory neurons. These are cells that produce gamma-aminobutyric acid (GABA), a chemical that dampens brain signals.

Conversely, the autism neurons show lower expression of genes that mark cells that produce glutamate, an excitatory signaling chemical, than in controls.

These results are intriguing because they suggest a lower ratio of excitatory to inhibitory signals than would normally be seen. Many studies have suggested that autism is characterized by exactly the opposite — that is, an overabundance of excitatory signals.

This discrepancy may be due to the age of the induced cells — the researchers tested them at 20 and 40 days old, which is early in human brain development. Mariani also points out that the excess GABA neurons may not all be functioning properly.

The researchers are focusing on the electrical signaling of the cells, Mariani says, “to see if they are functioning, if they have more inhibition, or if they have something strange happening.”

For more reports from the 2013 Society for Neuroscience annual meeting, please click here.

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Comments

Name: Jon Brock
12 November 2013 - 7:49PM

"This discrepancy may be due to the age of the induced cells — the researchers tested them at 20 and 40 days old, which is early in human brain development."

This is probably relevant:

Ben-Ari, Y., Khalilov, I., Kahle, K. T., & Cherubini, E. (2012). The GABA excitatory/inhibitory shift in brain maturation and neurological disorders. The Neuroscientist, 18(5), 467-486.

Name: Virginia Hughes
12 November 2013 - 7:58PM

Hi Jon,

The original Ben-Ari study on GABA function in newborns (showing excitatory activity, rather than inhibitory) concerned rats in the first 18 days of life. These ips experiments were all done at 20 and 40 days, so I think by then the GABA is presumably inhibitory...

Name: Jon Brock
12 November 2013 - 9:58PM

Although 18 days post-natal equates to about 40 days post-conception (he says, quickly googling "gestation rat")

Name: Emily Williams
12 November 2013 - 8:57PM

The identity of the cells may not be as trustworthy as their tendency to overproliferate, as many in vitro studies are poorly representative of what actually occurs in vivo in terms of cell identity. Too many local signals from tissue are necessary for proper differentiation. Not that the result isn't interesting, but it should be viewed skeptically until there is in vivo evidence to back it up.

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