The scientists studied cells from patients with Timothy syndrome, a rare genetic condition that is associated with one of the most penetrant forms of autism: In other words, most people with the Timothy syndrome mutation have autism as a symptom, among other problems.
In this study, the scientists suggest that the autism in Timothy syndrome patients is caused by a gene mutation that makes calcium channels in neuron membranes defective, interfering with how those neurons communicate and develop. The flow of calcium into neurons enables them to fire, and the way that the calcium flow is regulated is a pivotal factor in how our brains function.
The researchers also found brain cells grown from individuals with Timothy syndrome resulted in fewer of the kind of cells that connect both halves of the brain, as well as an overproduction of two of the brain's chemical messengers, dopamine and norepinephrine. Furthermore, they found they could reverse these effects by chemically blocking the faulty channels.
The gaps in our understanding of the causes of psychiatric disorders such as autism have made them difficult to treat. Perhaps the biggest obstacle to research into autism and other psychiatric and neurological diseases is that scientists cannot get living brain cell samples from people with these conditions, for obvious reasons. Doctor Ricardo Dolmetsch and his colleagues figured out a solution to this dilemma, using a novel approach involving what are known as induced pluripotent stem cells, or iPS cells.
The scientists grew these iPS cells as free-floating clumps in a nutrient-rich solution, later transferring the clumps to tissue culture plates. Here, some of them formed three-dimensional, brain like spheres whose cells later migrated outward and matured into neurons. These neurons formed three distinct layers, a good first approximation of living tissue in the brain. By visualising these neurons under a microscope and quantifying their gene expression, the scientists were able to characterise at the cellular level abnormalities that may be associated with autism.
The neurons grown from Timothy-syndrome iPS cells showed larger-than-normal spikes in calcium levels, suggesting the calcium channels lost their ability to shut off. This set off dramatic changes in neuronal signalling, reconfiguring how genes were expressed.
The cerebral cortex, the outer layer of the brain, has six distinct layers. In Timothy syndrome cell cultures, the proportion of neurons of specific layers differed from that in normal brains — additional biological evidence for the disorder. The neurons grown from the Timothy syndrome cells were less characteristic of lower-level neurons, which include neurons that bridge the left and right halves of the brain via the bundle of fibres known as the corpus callosum. This reinforces the view that autism results from defects in brain connectivity.
MEDICA.de; Source: Stanford University