Overview: Autism-associated genes overstimulate much larger brain cells in unmutated neurons.
sauce: Rutgers University
Scientists seeking to understand the underlying brain mechanisms of autism spectrum disorders have found that genetic mutations known to be associated with the disorder affect brain cells much larger than those found in neurons without mutations. was found to cause overstimulation of
The seven-year study led by Rutgers employed 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 study points to a potential new approach to studying brain disorders, the scientists say.
When describing a study in a journal, molecular psychiatryresearchers reported a mutation – R451C in the gene Neurorosin-3, It is known to cause autism in humans.
Quantified in experiments by scientists, this hyperexcitability manifests as bursts of electrical activity that are more than twice the level seen in unmutated brain cells.
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 College and senior author of the study, said: study.
“This gain of function in these specific cells, which our study reveals, causes an imbalance between neural networks in the brain, disrupting the normal flow of information.”
The mesh of interconnected cells that make up the human brain contains specialized ‘excitatory’ cells that stimulate electrical activity, balanced by ‘inhibitory’ brain cells that suppress electrical pulses. It’s been a long time coming, Mr Pang said. Scientists found that a burst of excessive electrical activity caused by the mutation threw the mouse’s brain helplessly.
Autism spectrum disorders are developmental disorders caused by differences in the brain. According to estimates by the Centers for Disease Control and Prevention, one in 44 of her children is confirmed to have the disorder.
According to the National Institute of Neurological Disorders and Stroke at the National Institutes of Health, research suggests that autism may be the result of a disruption of normal brain growth very early in development. According to the NIH, these disruptions may be the result of mutations in genes that control brain development and regulate how brain cells communicate with each other.
“Many of the underlying mechanisms of autism are unknown, hindering the development of effective treatments,” Pang said. “He wanted to use neurons generated from human stem cells as a model system to understand how and why specific mutations cause autism in humans.”
Researchers used CRISPR technology to alter the genetic material of human stem cells, create cell lines containing the mutation of interest, and derive human neuronal cells with this mutation. CRISPR, an acronym for Clustered Regularly Spaced Short Palindromic Repeats, is a unique gene-editing technology.
In this study, generated human neuronal cells (half mutated and half unmutated) were transplanted into mouse brains. From there, researchers measured and compared the electrical activity of specific neurons using electrophysiology, a branch of physiology that studies the electrical properties of living cells. Voltage changes or currents can be quantified on different scales, depending on the dimensions being studied.
“Our findings suggest that the NLGN3 R451C mutation dramatically affects excitatory synaptic transmission in human neurons, thereby causing changes in global network properties that may be relevant to psychiatric disorders.” We do,” Pang said. “We think this is very important information for the field.”
Pang said he hopes many of the techniques developed to conduct the experiment will be used in future scientific investigations into the basis of other brain disorders, such as schizophrenia. .
“This study highlights the potential of using human neurons as a model system to study psychiatric disorders and develop new treatments,” he said.
Other Rutgers scientists involved in the study include Le Wang, a postdoctoral fellow in Pan’s lab, and a PhD and medical degree as part of an MD-PhD student at Robert Wood Johnson Medical School. Acquiring Vincent Mirabella included. Assistant Professor Davide Comoletti, Postdoctoral Fellow Matteo Bernabucci, Xiao Su PhD Student, and Ishnoor Singh Graduate Student, all from New Jersey. He is a member of the Rutgers Child Health Institute. Professor Ronald Hart, Assistant Professors Peng Jiang and Kelvin Kwan, Postdoctoral Fellows Ranjie Shu and Azadeh Jadari, all in the Department of Cell Biology and Neuroscience at the Rutgers School of Arts and Sciences.
Thomas C. Südhof, a 2013 Nobel laureate and professor in the Department of Molecular and Cellular Physiology at Stanford University, contributed to this work, as did scientists at Central South University in Changsha, China. His SUNY Upstate Medical Center in Syracuse, New York. University of Massachusetts, Amherst, Massachusetts. Shaanxi Normal University in Shaanxi, China. Victoria University, Wellington, New Zealand.
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About this ASD and genetics research news
author: Patty Zielinski
sauce: Rutgers University
contact: Patti Zielinski – Rutgers University
image: image is public domain
Original research: closed access.
“Analysis of the autism-associated neuroligin-3 R451C mutation in human neurons reveals a gain-of-function synaptic mechanism’ Zhiping Pang et al. molecular psychiatry
Overview
Analysis of the autism-associated neuroligin-3 R451C mutation in human neurons reveals a gain-of-function synaptic mechanism
Mutations in many synaptic genes have been associated with autism spectrum disorders (ASD), suggesting that synaptic dysfunction is a key factor in ASD pathogenesis.Of these mutations, the R451C substitution is NLGN3 The gene encoding the postsynaptic adhesion molecule Neuroligin-3 is noteworthy because it is the first specific mutation associated with ASD.
on the mouse, the corresponding Nlgn3 The R451C-knockin mutation recapitulates the social interaction deficit in ASD patients and causes synaptic abnormalities, NLGN3 The R451C mutation in human neurons has not been investigated.
Here, we generated human knock-in neurons. NLGN3 R451C and NLGN3 null mutation.Surprisingly, an analysis of NLGN3 R451C mutant neurons revealed reduced R451C mutation NLGN3 Protein levels enhanced the strength of excitatory synapses without affecting inhibitory synapses.in the meantime NLGN3 Knockout neurons showed reduced excitatory synaptic strength.
Furthermore, overexpression of NLGN3 R451C recapitulated synaptic potentiation in human neurons. Notably, enhanced excitatory transmission was confirmed in vivo using human neurons transplanted into the mouse forebrain.
Use of co-cultured excitatory and inhibitory single-cell RNA-seq experiments NLGN3 In R451C mutant neurons, we identified differentially expressed genes in relatively mature human neurons that correspond to synaptic gene expression networks. In addition, gene ontology and enrichment analyzes revealed convergent gene networks associated with ASD and other psychiatric disorders.
Our findings are NLGN3 The R451C mutation induces gain-of-function enhancement of excitatory synaptic transmission that may contribute to the pathophysiology of ASD.
