Navigation Links
Scientists identify defect in brain cell channel that may cause autism-like syndrome
Date:11/27/2011

STANFORD, Calif. Neuroscientists at Stanford University School of Medicine have homed in on potential differences in autistic people's brain cells by studying brainlike spheres grown in an elaborate process from skin cells.

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.

Autism is a spectrum of developmental disorders of impaired social and verbal interaction. Currently, no medication exists to treat its underlying causes, according to the U.S. National Library of Medicine. Understanding what goes awry in autistic brain development could improve prospects for treating the condition.

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.

Postdoctoral scholar Sergiu Pasca, MD, and Ricardo Dolmetsch, PhD, associate professor of neurobiology, led the study, which will be published online Nov. 27 in Nature Medicine. Dolmetsch, a biophysicist, redirected his research to study autism after his son was diagnosed with Timothy syndrome. It's unclear what leads to autism, but its incidence is increasing, he said.

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 can't get living brain cell samples from people with these conditions, for obvious reasons. 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.

"We developed a way of taking skin cells from humans with Timothy syndrome and converting them into stem cells, then converting those stem cells into neurons," said Dolmetsch.

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, brainlike 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 visualizing these neurons under a microscope and quantifying their gene expression, the scientists were able to characterize 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 signaling, 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 fibers known as the corpus callosum. This reinforces the view that autism results from defects in brain connectivity.

Pasca and Dolmetsch had an "aha" moment when they realized the neurons grown from Timothy syndrome cells were making too much of the enzyme most critical for producing dopamine and norepinephrine, which play an important role in sensory processing and social behavior. The realization may offer important clues about what causes the problems seen in autism.

To determine whether the enzyme upsurge was reversible, the scientists treated the neurons with a chemical that blocks the defective calcium channels, called roscovitine. They saw a nearly 70 percent reduction in the proportion of cells producing the enzyme, confirming the defective calcium channel was the culprit in producing too much dopamine and norepinephrine. Such reversibility suggests that certain cellular abnormalities in autism may be treatable.

Dolmetsch warned, however, that roscovitine is not currently approved for use in humans and has never been tested in children. While it is currently in clinical trials for lung cancer, it reportedly causes nausea and other side effects. "The reported side effects are probably due to the fact that, in addition to targeting the channel that is mutated in autism, roscovitine also inhibits kinases that are required for cell proliferation," he said. "We think that roscovitine is a good starting point, but probably has to be optimized before it would be useful for autism."

In the meantime, the study represents a major achievement with its success in developing a technique to recreate how the neurons of individuals with Timothy syndrome develop in a lab setting. It's the first time it's been possible to study the disorder in human cells rather than mouse cells, so it represents a better clinical model, Dolmetsch said.

"These results could lead to a very powerful research tool," he said. "It's human psychiatric disease in a petri dish."


'/>"/>

Contact: Bruce Goldman
goldmanb@stanford.edu
650-725-2106
Stanford University Medical Center
Source:Eurekalert

Related medicine news :

1. Scientists Pinpoint Area of Brain That Fears Losing Money
2. Scientists Discover How HIV Is Transmitted Between Men
3. Prevention Is Key Research Goal for Premature Babies, Scientists Say
4. Scientists Discover Molecular Pathway for Organ Tissue Regeneration and Repair
5. Scientists find donut-shaped structure of enzyme involved in energy metabolism
6. Neuroscientists reveal new links that regulate brain electrical activity
7. Two UCSF Scientists to Receive Prestigious Dementia Research Honor
8. Johns Hopkins scientists develop personalized blood tests for cancer using whole genome sequencing
9. Scientists Spot Genetic Fingerprints of Individual Cancers
10. Scientists Unravel Mysteries of Intelligence
11. MSU scientists develop more effective method of predicting lead-poisoning risk
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:5/24/2017)... ... May 24, 2017 , ... Dr. Alan I. Benvenisty, MD is dual ... City. He is known for his distinguished expertise and experience in the diagnosis and ... sub-specialty training in treating renovascular disease and aortic aneurysm . He is known ...
(Date:5/24/2017)... ... May 24, 2017 , ... NucleusHealth ... interpretation, has received U.S. Food and Drug Administration (FDA) 510(k) clearance ... and secure cloud platform for medical image management. At the core is patented ...
(Date:5/24/2017)... ... 2017 , ... Dr. Manju R. Kejriwal, a leading Ohio dentist, is now ... a referral. Dr. Kejriwal understands the emotional and financial toll traditional orthodontics can take ... Patients no longer need to feel the esthetic effects of wires and brackets when ...
(Date:5/24/2017)... ... May 24, 2017 , ... ... Policy Solutions is vehemently opposed to Donald Trump’s budget, “A New Foundation for ... that inspires fear, demonizes the poor, marginalizes underserved populations, undermines productivity, and destroys ...
(Date:5/24/2017)... ... May 24, 2017 , ... ... Course II of the HP3 (High-Performance Periodontal Practice) continuing education (CE) series. As ... latest advancements in his field by attending numerous CE courses each year. His ...
Breaking Medicine News(10 mins):
(Date:5/9/2017)... , May 9, 2017  Semler Scientific, Inc. ... technology solutions to improve the clinical effectiveness and ... for the first quarter ended March 31, 2017. ... enable our customers to identify when preventive care ... before events like heart attacks or strokes occur," ...
(Date:5/6/2017)... --  Provista , a proven leader in the supply chain ... Jim Cunniff as the company,s new president and ... to Provista, including most recently serving as the president and ... . He assumed his new role with Provista on May ... Provista," says Jody Hatcher , president, Sourcing and Collaboration ...
(Date:5/4/2017)... MONTREAL , May 4, 2017  Fortuna Fix Inc. (" ... aiming to be the first to eliminate the need for ... autologous cells to treat neurodegenerative diseases. Fortuna ... ("SAB") with Professor Michael Fehlings , MD, PhD; Father ... Hack , MD, MPH; and Professor James Giordano , ...
Breaking Medicine Technology: