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    Gene Mutation Leading To Autism Found to Overstimulate Brain Cells

    Summary: A gene associated with autism overstimulates brain cells far greater in neurons without the mutation.

    Source: Rutgers University

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

    The Rutgers-led study, spanning seven years, 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 work illustrates the potential of a new approach to studying brain disorders, scientists said.

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

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

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

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

    The interconnected mesh of cells that constitutes the human brain contains specialized “excitatory” cells that stimulate electrical activity, balanced by “inhibitory” brain cells that curtail electrical pulses, Pang said. The scientists found the oversized burst of electrical activity caused by the mutation threw the mouse brains out of kilter.

    Autism spectrum disorder is a developmental disability 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 autism could be a result of disruptions in normal brain growth very early in development, according to the National Institutes of Health’s National Institute of Neurological Disorders and Stroke. 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.

    “So much of the underlying mechanisms in autism are unknown, which hinders the development of effective therapeutics,” 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.”

    Researchers employed CRISPR technology to alter the human stem cells’ genetic material to create a line of cells containing the mutation they wanted to study, and then derived human neuron cells carrying this mutation. CRISPR, an acronym for clustered regularly interspaced short palindromic repeats, is a unique gene-editing technology.

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

    In the study, the human neuron cells that were generated, half with the mutation, half without, were then implanted in the brains of mice. From there, researchers measured and compared the electrical activity of specific neurons employing electrophysiology, a branch of physiology that studies the electrical properties of biological cells. Voltage changes or electrical current can be quantified on a variety of scales, depending on the dimensions of the object of study.

    “Our findings suggest that the NLGN3 R451C mutation dramatically impacts excitatory synaptic transmission in human neurons, thereby triggering changes in overall network properties that may be related to 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 of using human neurons as a model system to study mental disorders and develop novel therapeutics,” 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 Robert Wood Johnson Medical School; Davide Comoletti, an assistant professor, Matteo Bernabucci, a postdoctoral fellow, Xiao Su, a doctoral student, and Ishnoor Singh, a graduate student, all of the Rutgers Child Health Institute of New Jersey; Ronald Hart, a professor, Peng Jiang and Kelvin Kwan, assistant professors, and Ranjie Xu and Azadeh Jadali, postdoctoral fellows, all of 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 at Central South University in Changsha, China; SUNY Upstate Medical Center in Syracuse, N.Y.; University of Massachusetts in 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 Zielinski
    Source: Rutgers University
    Contact: Patti Zielinski – Rutgers Univesity
    Image: The image is in the public domain

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


    Abstract

    Analyses of the autism-associated neuroligin-3 R451C mutation in human neurons reveal a gain-of-function synaptic 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 the NLGN3 gene that encodes the postsynaptic adhesion molecule Neuroligin-3 is noteworthy because it was the first specific mutation linked to ASDs.

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

    Here, we generated human knockin neurons with the NLGN3 R451C and NLGN3 null mutations. Strikingly, analyses of NLGN3 R451C-mutant neurons revealed that the R451C mutation decreased NLGN3 protein levels but enhanced the strength of excitatory synapses without affecting inhibitory synapses; meanwhile NLGN3 knockout neurons showed reduction in excitatory synaptic strengths.

    Moreover, overexpression of NLGN3 R451C recapitulated the synaptic enhancement in human neurons. Notably, the augmentation of excitatory transmission was confirmed in vivo with human neurons transplanted into 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 corresponding to synaptic gene expression networks. Moreover, gene ontology and enrichment analyses revealed convergent gene networks associated with ASDs and other mental disorders.

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

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