Autism, like other complex neuronal disorders, is usually attributable to the interaction of multiple genetic and environmental factors that have been extremely difficult to tease apart. People with Timothy syndrome suffer from hypoglycemia, cardiac arrhythmia, and global developmental delay; more than 60 percent of them also have an autism spectrum disorder (ASD). Researchers in California and Japan recently generated stem cells from people with Timothy syndrome and began differentiating them into neurons in an attempt to gain further insights into autism. Their results are published in Nature Medicine.

Timothy syndrome is caused by a genetic mutation that changes one amino acid in a calcium channel expressed in the brain—calcium influx through these channels is essential for neuronal processes. It is not yet known how the mutation that causes Timothy syndrome disrupts normal cellular functioning or how it leads to psychiatric symptoms. Timothy syndrome thus provides a good system for examining how a specific gene contributes to brain development.

The mutation that causes Timothy syndrome prevents the channel from shutting down in response to cellular changes, meaning the channel is active more than it should be. Neurons made from Timothy stem cells exhibited an increased rise in calcium. After their mutated channels let calcium flood in, these cells retained more calcium, and did so for a longer time, than control neurons with normal channels.

Since calcium influx through these channels is known to impact the regulation of gene expression, the researchers compared the gene expression profiles of Timothy neurons and control neurons. The expression of hundreds of genes were found to be altered in Timothy neurons and neuronal precursor cells, and eleven of these genes had previously been implicated in either ASDs or other intellectual disabilities.

Analysis of the types of genes over- or under-expressed in the Timothy syndrome neurons confirmed that the mutation leads to the disregulation of genes that have calcium-regulated expression. These included the genes that produce catecholamines, including dopamine and norepinephrine. As a result, Timothy syndrome neurons secrete twice as much dopamine and three times as much norepinephrine than control neurons. As these neurotransmitters have important social functions, their increased synthesis could play a role in the development of ASDs.

The Timothy cells also had an altered profile of neuronal differentiation markers, with the changes suggesting that Timothy neurons would preferentially target different areas of the brain. This is consistent with an emerging idea among those who study ASDs, namely that they arise from defects in the connectivity between cortical areas.

The autism seen in Timothy syndrome is unusual, because it is caused by a single, known genetic mutation. Now that some of the functional steps between the genetic mutation and the neurodevelopmental disorder have been elucidated in this study, perhaps they can shed light on the causes of autism in people without Timothy syndrome as well.

Nature Medicine, 2011. DOI: 10.1038/nm.2576 (About DOIs).