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Gene mutation leading to autism found to overstimulate brain cells – Neuroscience News

Summary: A gene associated with autism overstimulates brain cells significantly more in neurons without mutation.

Source: Rutgers University

Scientists seeking to understand the basic brain mechanisms of autism spectrum disorder have discovered that a genetic mutation known to be associated with the disorder causes brain cells to be overstimulated far greater than that seen in neuronal cells without the mutation.

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

The work illustrates the potential for a new approach to studying brain disorders, the scientists said.

Describing the study in the journal, Molecular psychiatrythe researchers reported a mutation – R451C in the gene Neurologin-3, known to cause autism in humans – was found to cause a higher level of communication among a network of human brain cells transplanted into mouse brains.

This over-excitement, quantified in experiments by the scientists, manifests as a burst of electrical activity more than double the level seen in brain cells without the mutation.

“We were surprised to find an improvement, not a deficit,” said Zhiping Pang, associate professor in the Department of Neuroscience and Cell Biology at the New Jersey Institute of Child Health at Rutgers Robert Wood Johnson Medical School and author. principal of the study. study.

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

The interconnected mesh of cells that makes up the human brain contains specialized “excitatory” cells that stimulate electrical activity, balanced by “inhibitory” brain cells that reduce electrical impulses, Pang said. The scientists found that the burst of oversized electrical activity caused by the mutation had thrown the mouse’s brain out of whack.

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

Studies suggest that autism may be the result of disruptions in normal brain growth very early in development, according to the National Institute of Neurological Disorders and Stroke at the National Institutes of Health. These disturbances 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.

“Much of the mechanisms underlying autism are unknown, which hampers the development of effective therapies,” Pang said. “Using human neurons generated from human stem cells as a model system, we wanted to understand how and why a specific 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, then derived human neuron cells carrying that mutation. CRISPR, an acronym for Clustered Regularly Spaced Short Palindromic Repeats, is a unique gene-editing technology.

It shows a brain
The work illustrates the potential for a new approach to studying brain disorders, the scientists said. Image is in public domain

In the study, human neural cells that were generated half with the mutation, half without, 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. Changes in voltage or electric current can be quantified at different scales, depending on the dimensions of the object under study.

“Our results suggest that the NLGN3 R451C mutation dramatically impacts excitatory synaptic transmission in human neurons, thereby triggering changes in global network properties that may be linked to mental disorders,” Pang said. “We see this as very important information for the pitch.”

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

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

Other Rutgers scientists involved in the study include Le Wang, a postdoctoral associate in Pang’s lab, and Vincent Mirabella, who is earning doctoral and medical degrees as part of the MD-PhD student at the Robert Wood Johnson Medical School; Davide Comoletti, assistant professor, Matteo Bernabucci, postdoctoral fellow, Xiao Su, doctoral candidate, and Ishnoor Singh, graduate student, all from the Rutgers Child Health Institute of New Jersey; Ronald Hart, professor, Peng Jiang and Kelvin Kwan, assistant professors, and Ranjie Xu and Azadeh Jadali, postdoctoral fellows, all from the Department of Cell Biology and Neurosciences, Rutgers School of Arts and Sciences.

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

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About this ASD and Genetics Research News

Author: Patti Zielinsky
Source: Rutgers University
Contact: Patti Zielinski – Rutgers University
Image: Image is in public domain

Original research: Access closed.
“Analysis of autism-associated neuroligin-3 R451C mutation in human neurons reveals synaptic gain-of-function mechanism” by Zhiping Pang et al. Molecular psychiatry


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

Mutations in many synaptic genes are associated with autism spectrum disorder (ASD), suggesting that synaptic dysfunction is a key factor in the pathogenesis of ASD. Among these mutations, the R451C substitution in the NLGN3 The gene that codes for the post-synaptic adhesion molecule Neuroligin-3 is notable because it is the first specific mutation linked to ASDs.

In mice, the corresponding Nlgn3 The R451C-knockine mutation recapitulates the social interaction deficits of patients with ASD and produces synaptic abnormalities, but the impact of NLGN3 The R451C mutation on human neurons has not been studied.

Here we generated human knockin neurons with the NLGN3 R451C and NLGN3 null mutations. Surprisingly, analyzes of NLGN3 Mutant R451C neurons revealed that the R451C mutation decreases NLGN3 protein levels but improved the strength of excitatory synapses without affecting inhibitory synapses; during this time NLGN3 knockout neurons showed reduced excitatory synaptic forces.

Moreover, overexpression of NLGN3 R451C recapitulated synaptic enhancement in human neurons. Notably, the increase in excitatory transmission has been confirmed in vivo with human neurons transplanted into the forebrain of mice.

Using single-cell RNA-seq experiments with co-cultured exciters and inhibitors NLGN3 Mutant R451C neurons, we identified differentially expressed genes in relatively mature human neurons corresponding to synaptic gene expression networks. Additionally, gene ontology and enrichment analyzes revealed convergent gene networks associated with ASD and other mental disorders.

Our findings suggest that the NLGN3 The R451C mutation induces an enhanced gain-of-function in excitatory synaptic transmission that may contribute to the pathophysiology of ASD.

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