Neurons grown from skin cells may hold clues to autism
Rare syndrome's workings could help explain how brain wiring goes awry — NIH-funded study
Potential clues to how autism miswires the brain are emerging from a study of a rare, purely genetic form of the disorders that affects fewer than 20 people worldwide. Using cutting-edge “disease-in a-dish” technology, researchers funded by the National Institutes of Health have grown patients' skin cells into neurons to discover what goes wrong in the brain in Timothy Syndrome. Affected children often show symptoms of autism spectrum disorders along with a constellation of physical problems.
Abnormalities included changes in the composition of cells in the cortex, the largest brain structure in humans, and of neurons that secrete two key chemical messengers. Neurons that make long-distance connections between the brain’s hemispheres tended to be in short supply.
Most patients with Timothy Syndrome meet diagnostic criteria for an autism spectrum disorder. Yet, unlike most cases of autism, Timothy syndrome is known to be caused by a single genetic mutation.
Prior to the current study, researchers knew that Timothy syndrome is caused by a tiny glitch in the gene that codes for a calcium channel protein in cell membranes. The mutation results in too much calcium entering cells, causing a tell-tale set of abnormalities throughout the body. Proper functioning of the calcium channel is known to be particularly critical for proper heart rhythm — many patients die in childhood of arrhythmias — but its role in brain cells was less well understood.
To learn more, Dolmetsch and colleagues used a new technology called induced pluripotent stem cells (iPSCs). They first converted skin cells from Timothy Syndrome patients into stem cells and then coaxed these to differentiate into neurons.
Many of these defects were also seen in parallel studies of mice with the same genetic mutation found in Timothy syndrome patients. This supports the link between the mutation and the developmental abnormalities.
Several genes previously implicated in autism were among hundreds found to be expressed abnormally in Timothy Syndrome neurons. Excess cellular calcium levels also caused an overproduction of neurons that make key chemical messengers. Timothy Syndrome neurons secreted 3.5 times more norepinephrine and 2.3 times more dopamine than control neurons. Addition of a drug that blocks the calcium channel reversed the abnormalities in cultured neurons, reducing the proportion of catecholamine-secreting cells by 68 percent.
The findings in Timothy Syndrome patient iPSCs follow those in Rett Syndrome, another single gene disorder that often includes autism-like symptoms. About a year ago, Alysson Muotri, Ph.D., and colleagues at University of California, San Diego, reported deficits in the protrusions of neurons, called spines, that help form connections, or synapses. The Dolmetsch team’s discovery of earlier (neuronal fate) and later (altered connectivity) defects suggest that disorders on the autism spectrum affect multiple stages in early brain development.
The mechanisms identified in this study may become potential targets for developing new therapies for Timothy Syndrome and may also provide insights into the neural basis of deficits in other forms of autism, said Dolmetsch.