Autism-like syndrome could explain how brain wiring goes awry
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.
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.
"Studying the consequences of a single mutation, compared to multiple genes with small effects, vastly simplifies the task of pinpointing causal mechanisms," Ricardo Dolmetsch, lead author of the study, said.
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 his 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.
"Remarkable reproducibility" observed across multiple iPSC lines and individuals confirmed that the technique can reveal defects in neuronal differentiation like whether cells assume the correct identity as the brain gets wired-up in early development, said the researchers.
Compared to those from controls, fewer neurons from Timothy Syndrome patients became neurons of the lower layers of the cortex and more became upper layer neurons. The lower layer cells that remained were more likely to be the kind that project to areas below the cortex.
In contrast, there were fewer-than-normal neurons equipped to form a structure, called the corpus callosum, which makes possible communications between the left and right hemispheres.
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 study has been recently published in Nature Medicine. (ANI -Posted on / )
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