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

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

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

Abstract: A gene linked to autism overstimulates brain cells far more in neurons without the mutation.

Source: Rutgers University

Scientists seeking to understand the underlying brain mechanisms of autism spectrum disorder have found that a gene mutation known to be associated with the disorder causes overstimulation of brain cells far greater than that seen in neuronal cells without the mutation.

The Rutgers-led study, which spanned seven years, used some of the most advanced approaches available in scientific tools, including growing human brain cells from stem cells and transplanting them into the brains of mice.

The work illustrates the potential of a new approach to studying brain disorders, the researchers said.

Describing the study in the journal, Molecular psychiatryresearchers reported a mutation – R451C in the gene neurologin-3, known to cause autism in humans – was found to induce higher levels of communication among a network of transplanted human brain cells in the brains of mice.

This overexcitation, which the scientists quantified in experiments, manifests as a burst of electrical activity more than twice the level seen in brain cells without the mutation.

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

“This gain in function in these specific cells, which our study found, causes an imbalance among the brain’s neuronal network, disrupting the normal flow of information.”

The interconnected network of cells that make 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 excessive burst of electrical activity caused by the mutation threw the mouse’s brain into disarray.

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

Studies suggest that autism may result from a disruption of normal brain growth very early in development, according to the National Institutes of Health’s National Institute of Neurological Disorders and Stroke. These disorders can result from mutations in genes that control brain development and regulate the way brain cells communicate with each other, according to the NIH.

“Many of the mechanisms underlying autism are unknown, which hampers the development of effective therapies,” said Pang. “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 neuron cells that carried the mutation. CRISPR, an acronym for clustered regularly spaced short palindromic repeats, is a unique gene editing technology.

A gene mutation that leads to autism has been found to overstimulate brain cells
The work illustrates the potential of a new approach to studying brain disorders, the researchers said. The image is in the public domain

In the study, human neuronal cells were created, half with the mutation, half without the mutation, then implanted into the brains of mice. From there, the researchers measured and compared the electrical activity of specific neurons using electrophysiology, the branch of physiology that studies the electrical properties of biological cells. Changes in voltage or electric current can be quantified on different scales, depending on the dimensions of the object of study.

“Our findings suggest that the NLGN3 R451C mutation dramatically affects excitatory synaptic transmission in human neurons, thereby triggering changes in overall network properties that may be associated with mental disorders,” Pang said. “We consider this very important information for the field.”

Pang said he expects many of the techniques developed to conduct this experiment will be used in future scientific research 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 mental disorders and develop new therapeutics,” he said.

Other Rutgers scientists involved in the study include Le Wang, a postdoctoral fellow in Pang’s lab, and Vincent Mirabello, who is earning his doctorate and medical degrees as part of his MD at the Robert Wood Johnson School of Medicine; Davide Comoletti, assistant professor, Matteo Bernabucci, postdoctoral fellow, Xiao Su, doctoral student, 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 Neuroscience, 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 the study, as did scientists from Central South University in Changsha, China; SUNY Upstate Medical Center in Syracuse, NY; University of Massachusetts at Amherst, Massachusetts; Shaanxi Normal University in Shaanxi, China; and Victoria University of Wellington, New Zealand.

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About this ASD and genetic research news

Author: Patti Zielinski
Source: Rutgers University
Contact: Patti Zielinski – Rutgers University
Picture: The image is in the public domain

Original research: Closed access.
Analyzes of autism-associated neuroligin-3 R451C mutation in human neurons reveal a synaptic gain-of-function mechanism” Zhiping Pang et al. Molecular psychiatry


Abstract

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

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

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

Here, we generated human tapping neurons with NLGN3 R451C and NLGN3 zero mutations. Amazingly, the analysis of NLGN3 R451C-mutated neurons revealed that the R451C mutation decreased NLGN3 protein levels, but enhanced the strength of excitatory synapses without affecting inhibitory synapses; in the meantime NLGN3 knockout neurons showed a decrease in excitatory synaptic strength.

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

Using single-cell RNA-seq experiments with co-cultured excitatory and inhibitory NLGN3 R451C-mutant neurons, we identified differentially expressed genes in relatively mature human neurons that correspond to synaptic gene expression networks. Moreover, gene ontology and enrichment analyzes revealed convergent gene networks associated with ASD and other mental disorders.

Our findings suggest that NLGN3 The R451C mutation causes a gain of function in excitatory synaptic transmission that may contribute to the pathophysiology of ASD.

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