Rutgers-led work highlights the potential of new techniques to study mental disorders.
Scientists trying to understand the basic brain mechanisms of autism spectrum disorder have found that a gene mutation known to be associated with the disorder causes much greater overstimulation in brain cells than is seen in neuronal cells without the mutation.
The seven-year study led by Rutgers used some of the most advanced approaches available in the scientific toolbox, including growing human brain cells from stem cells and transplanting them into mouse brains.
The scientists said the study shows the potential of a new approach to study brain disorders.
describing Researchers in the study in the journal Molecular Psychiatry found that the R451C mutation in the Neurologin-3 gene, which is known to cause autism in humans, causes a higher communication between the network of human brain cells transplanted in mouse brains. This overstimulation, which the scientists measured in their experiments, manifests as a burst of electrical activity more than twice the level seen in unmutated brain cells.
«We were surprised to find an improvement, not a deficit,» he said. Zhiping PangAssociate Professor in the Department of Neuroscience and Cell Biology at the New Jersey Institute of Child Health. Rutgers Robert Wood Johnson School of Medicine and senior author of the study. «What our study reveals is that this gain of function in these particular cells causes an imbalance among the brain’s neuronal network, disrupting the normal flow of information.»
Pang said the interconnected network of cells that make up the human brain contains special «exciter» cells that stimulate electrical activity, which is balanced by «inhibitory» brain cells that reduce electrical impulses. The scientists found that the enormous burst of electrical activity caused by the mutation sent mouse brains out of control.
Autism spectrum disorder is a developmental disability that results from differences in the brain. According to the estimates of the Centers for Disease Control and Prevention, about 1 in 44 children has the disorder.
According to the National Institute of Neurological Disorders and Stroke at the National Institutes of Health, research indicates that autism may be the result of disruptions in normal brain growth very early in development. These disruptions may be the result of mutations in genes that control brain development and regulate how brain cells communicate with each other, according to the NIH.
«Many of the underlying mechanisms in autism are unknown, which hinders the development of effective therapeutics,» said Pang. «Using human neurons produced from human stem cells as a model system, we wanted to understand how and why a particular mutation causes autism in humans.»
The researchers used CRISPR technology to modify the genetic material of human stem cells to create a cell line containing the mutation they wanted to study, and then generate human neuron cells that carry that mutation. CRISPR, short for clustered, regularly spaced short palindromic repeats, is a unique gene editing technology.
In the study, human neuron cells, half with mutations and half without mutations, were then implanted into the brains of mice. From there, the researchers measured and compared the electrical activity of specific neurons using electrophysiology, a branch of physiology that studies the electrical properties of biological cells. Voltage changes or electric current can be measured at various scales, depending on the dimensions of the object under study.
«Our findings suggest that the NLGN3 R451C mutation significantly affects excitatory synaptic transmission in human neurons, thereby triggering changes in overall network properties that may be relevant to mental disorders,» said Pang. «We see this as very important information for the field.»
Pang said he expects many of the techniques developed to run this experiment be used in future scientific research on the basis of other brain disorders such as schizophrenia.
«This work highlights the potential to use human neurons as a model system to study mental disorders and develop new therapeutics,» he said.
Other Rutgers scientists involved in the study include Le Wang, a postdoctoral associate. Pang’s laband Vincent Mirabella, who earned doctorate and medical degrees as part of an MD-PhD student at the Robert Wood Johnson School of Medicine; Davide Comoletti, assistant professor, Matteo Bernabucci, postdoctoral fellow, Xiao Su, PhD student and graduate student Ishnoor Singh, the entire Rutgers Institute of Child Health, New Jersey; Ronald Hart, a professor, Peng Jiang and Kelvin Kwan, assistant professors, and Ranjie Xu and Azadeh Jadali, postdoctoral researchers, Rutgers School of Arts and Sciences, Department of Cell Biology and Neuroscience.
Thomas C. Südhof, a 2013 Nobel laureate and professor in the Department of Molecular and Cellular Physiology at Stanford University, contributed to the research, as did scientists at Central South University in Changsha, China; SUNY Upstate Medical Center in Syracuse, NY; University of Massachusetts, Amherst, Mass.; Shaanxi Normal University in Shaanxi, China; and Victoria University of Wellington, New Zealand.
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