The gene mutation that leads to autism has been found to overstimulate brain cells

Summary: A gene linked to autism overexcites brain cells much more in neurons that do not contain the mutation.

source: Rutgers University

Scientists looking to understand the underlying brain mechanisms of autism spectrum disorder have discovered that a genetic mutation known to be associated with the disorder results in much greater overstimulation of brain cells than neurons without the mutation.

The seven-year Rutgers-led study used some of the most advanced methods available in the scientific toolbox, including growing human brain cells from stem cells and transplanting them into the brains of mice.

Scientists said the work illustrates the potential of a new approach to studying brain disorders.

Description of the study in the journal, Molecular Psychiatrythe researchers report a -R451C mutation in the gene neurologen-3, It is known to cause autism in humans – it was found to trigger a higher level of connectivity between a network of human brain cells implanted in the brains of mice.

This overexcitation, measured in the scientists’ experiments, manifests itself as a burst of electrical activity more than twice the level seen in brain cells without the spike.

said Zipeng Pang, associate professor in the department of neuroscience and cell biology at the New Jersey Institute of Child Health at Rutgers Robert Wood Johnson School of Medicine and senior author of the study.

“This gain of function in those specific cells, revealed by our study, causes an imbalance among the network of neurons in the brain, disrupting the normal flow of information.”

The interconnected network of cells that make up the human brain, Pang said, contains specialized “excitatory” cells that stimulate electrical activity, balanced by “inhibitory” brain cells that reduce electrical impulses. The scientists found that the huge burst of electrical activity caused by the surge snapped the mouse brains out of their unstable state.

Autism spectrum disorder is a developmental disability caused by differences in the brain. About 1 in 44 children has been identified with the disorder, according to estimates from the Centers for Disease Control and Prevention.

Studies show that autism can be the result of disruptions in normal brain development very early in development, according to the National Institute of Neurological Disorders and Stroke of the National Institutes of Health. These disorders may be the result of mutations in genes that control brain development and regulate how brain cells communicate with each other, according to the National Institutes of Health.

“Many of the mechanisms underlying autism are unknown, which hinders the development of effective treatments,” Pang said. “Using human neurons generated 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 alter the genetic material of human stem cells to create a cell line that contained the mutation they wanted to study, and then derived human neurons that carried the mutation. CRISPR, which is short for regularly alternating short palindromic repeat, is a unique gene-editing technology.

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Scientists said the work illustrates the potential of a new approach to studying brain disorders. The image is in the public domain

In the study, the human neurons that were created, half with the mutation, and half without the mutation, were transplanted 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 or electric current changes can be measured on a variety of scales, depending on the dimensions of the subject of study.

“Our findings indicate that the NLGN3 R451C mutation significantly affects excitatory synaptic transmission in human neurons, inducing changes in overall network properties that may be associated with mental disorders,” Pang said. “We view this as very important information for the field.”

Pang said he expects many of the techniques developed to conduct this experiment to be used in future scientific investigations into the basis of other brain disorders, such as schizophrenia.

“This study highlights the potential to use human neurons as a model system to study mental disorders and develop new therapies,” he said.

Other Rutgers scientists involved in the study include Lu Wang, a postdoctoral fellow in Pang’s lab, and Vincent Mirabella, a PhD and MD as part of an MD student at Robert Wood Johnson Medical School. Davide Comoletti, assistant professor, Matteo Bernabucci, postdoctoral fellow, Xiao Su, doctoral student, and Ishnur Singh, graduate student, all from the Rutgers Institute of Child Health in New Jersey; Ronald Hart, Professor, Peng Jiang and Kelvin Kwan, Assistant Professor, and Ranji Xu and Azadeh Jadali, Postdoctoral Fellows, are all from the Department of Cell Biology and Neuroscience, Rutgers School of Arts and Sciences.

Thomas C. Sudhoff, a 2013 Nobel Prize laureate and professor in the Department of Molecular and Cellular Physiology at Stanford University, contributed to the study, as did scientists at Central South University in Changsha, China; SUNY Upstate Medical Center in Syracuse, New York; University of Massachusetts in Amherst, Massachusetts; Shaanxi Normal University in Shaanxi, China; and Victoria University of Wellington, New Zealand.

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About this ASD and genetics research news

author: Patty Zelensky
source: Rutgers University
Contact: Patty Zelensky – Rutgers University
picture: The image is in the public domain

Original search: Closed access.
“Analyses of the autism-associated neuroligin-3 R451C mutation in human neurons reveal a synaptic mechanism of gain-of-function” by Zhiping Pang et al. Molecular Psychiatry


Summary

Analyzes of the autism-associated neuroligin-3 R451C mutation in human neurons reveal a synaptic mechanism of gain-of-function.

Mutations in several synaptic genes are associated with autism spectrum disorders (ASD), suggesting that synaptic dysfunction is a major driver of ASD pathogenesis. Among these mutations, the R451C substitution was in NLGN3 The gene encoding the postsynaptic adhesion molecule Neuroligin-3 is noteworthy because it was the first identified mutation associated with ASDs.

in the corresponding mice Nlgn3 The R451C-knockin mutation recapitulates the social interaction deficits of ASD patients and produces synaptic abnormalities, but the effect of NLGN3 The R451C mutation has not been investigated on human neurons.

Here, we created human neurons with NLGN3 R451C f NLGN3 null mutations. Remarkably, analytics NLGN3 R451C mutant neurons revealed that the R451C mutation was decreased NLGN3 protein levels but enhanced the strength of excitatory synapses without affecting inhibitory synapses; at the same time NLGN3 The knockdown neurons showed a decrease in excitatory synaptic forces.

Moreover, overexpression of NLGN3 R451C recapitulated synaptic reinforcement in human neurons. Notably, increased excitatory transmission was confirmed in vivo by transplantation of human neurons into the mouse forebrain.

Using single-cell RNA-seq experiments with co-excitatory and inhibitory cell excitation NLGN3 R451C-transformed neurons, we identified differentially expressed genes in relatively mature human neurons corresponding to synaptic gene expression networks. Furthermore, epigenetic ontology and enrichment analyzes revealed convergent genetic networks associated with autism and other mental disorders.

Our results indicate that NLGN3 The R451C mutation induces enhanced gain-of-function in excitatory synaptic transmission that may contribute to the pathophysiology of autism spectrum disorder.

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