Highlighting the potential of new techniques to study mental disorders

Researchers investigating the fundamental brain mechanics of autism spectrum disorder have discovered that a gene mutation known to be connected with the illness causes considerably more overstimulation of brain cells than in neuronal cells without the mutation.

The seven-year study led by Rutgers used some of the most cutting-edge techniques in the scientific toolbox, such as generating human brain cells from stem cells and transferring them into mouse brains.

According to the researchers, the finding demonstrates the possibility of a novel technique to investigate brain disorders.

Investigators reported in the journal Molecular Psychiatry that a mutation—R451C in the gene Neurologin-3, known to cause autism in humans—was shown to increase communication among a network of transplanted human brain cells in mice brains.

The scientists’ investigations show that this overexcitation presents itself as a burst of electrical activity that is more than double the level seen in brain cells that do not have the mutation.

We were surprised to find an enhancement, not a deficit. 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.”

Zhiping Pang, Study Senior Author and Associate Professor, Department of Neuroscience and Cell Biology, Child Health Institute of New Jersey, Robert Wood Johnson Medical School

The human brain’s interwoven mesh of cells comprises specialized “excitatory” cells that promote electrical activity, which is balanced by “inhibitory” brain cells that limit electrical pulses, according to Pang. The scientists discovered that the enlarged surge of electrical activity induced by the mutation knocked the mouse brains off balance.

Autism spectrum disorder is a developmental impairment caused by brain abnormalities. According to the Centers for Disease Control and Prevention, around one in every 44 children has the disorder.

According to the National Institutes of Health’s National Institute of Neurological Disorders and Stroke, research suggests that autism may be caused by disturbances in normal brain growth very early in development. According to the NIH, these abnormalities could be caused by mutations in genes that affect brain growth and influence how brain cells communicate with one another.

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

Zhiping Pang, Study Senior Author and Associate Professor, Department of Neuroscience and Cell Biology, Child Health Institute of New Jersey, Robert Wood Johnson Medical School

The investigators used CRISPR technology to modify the genetic material of human stem cells to produce a line of cells bearing the mutation they wished to explore and then produced human neuron cells harboring this mutation. CRISPR, which stands for clustered regularly interspaced short palindromic repeats, is a one-of-a-kind gene-editing technique.

The human neuron cells generated in the research were implanted in the brains of mice, half with the mutation and half without. The researchers next used electrophysiology, a branch of physiology that investigates the electrical properties of biological cells, to assess and compare the electrical activity of individual neurons. Based on the dimensions of the object of investigation, voltage changes or electrical current can be evaluated on a variety of scales.

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. We view this as very important information for the field.”

Zhiping Pang, Study Senior Author and Associate Professor, Department of Neuroscience and Cell Biology, Child Health Institute of New Jersey, Robert Wood Johnson Medical School

Many of the approaches employed to carry out this experiment, according to Pang, will be applied in future scientific investigations into the basis of other brain disorders, like schizophrenia.

Pang concludes, “This study highlights the potential of using human neurons as a model system to study mental disorders and develop novel therapeutics.”

Source:
Journal reference:

Wang, L., et al. (2022) Analyses of the autism-associated neuroligin-3 R451C mutation in human neurons reveal a gain-of-function synaptic mechanism. Molecular Psychiatry. doi.org/10.1038/s41380-022-01834-x.

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