A new study published in the Journal of Molecular Psychiatry looked at an autism-associated mutation in human neurons.

“In this study, we are trying to understand the mechanism underlying a genetic mutation linked to autism,” Dr. Le Wang, lead author, told us. “Since the gene is involved in the information flow in the brain, we wanted to find out if the genetic mutation leads to abnormal information flow in humans using a human neural model.”

According to the Centers for Disease Control and Prevention, approximately one in 44 children in the U.S. have been diagnosed with autism. Autism doesn’t discriminate. It has been found in all racial, socioeconomic and ethnic populations, however minority groups have a tendency to be diagnosed later and less often. Male children are four times more likely to be diagnosed with autism than female children. An average of one in 27 male children are diagnosed with autism while one in 116 female children have autism.

The earliest a child can be diagnosed with autism is age two, however most children are identified after the age of four. Over 30 per cent of children with autism also have an intellectual disability and over 40 per cent have IQ scores in the average to above average range. There is no medical detection for autism such as a blood test, and early intervention has shown to be the best way to obtain the best outcome for children with autism.
From the previous studies in animal models, the researchers initially hypothesized that they would find a loss-of-function, i.e., a reduction in synaptic transmission.

“However, our result speaks the opposite,” Dr. Wang told us. “We found an enhancement in synaptic transmission that excites the cell more in human neurons carrying the gene mutation.”

The gene the research team was studying is called Neuroligin-3. A mutation in this gene, i.e., R451C, was the first single-gene mutation identified in a boy with autism. Despite many studies using animal models that showed impaired neuronal communication, it is still being determined whether the results from the animal studies can be translated into humans.

To test their theory, the researchers used CRISPR gene editing technology, engineered human stem cells carrying this mutation, made neurons from these stem cells, and then studied these human neurons with such a mutation.

“We found that the neuronal communication mediated by excitatory neurons is enhanced in the R451C-mutant human neurons in a culture dish and human neurons transplanted animals,” study author, Dr. Zhiping Pang told us. “We were surprised to find an enhancement, not a deficit.”

The gain-of-function in those specific cells, revealed by the study, causes an imbalance in the brain’s neuronal network, disrupting the normal information flow. The results of the study highlight the potential of using human neurons as a model system to study mental disorders and develop novel therapeutics.

“There is a high prevalence of mental disorders, and the pandemic will likely worsen the situation,” Dr. Pange told us. “The only way to cure these devastating disorders is via scientific research. We hope more investment will be put into understanding our brain in health and disease. I also hope that our study will contribute to developing novel therapeutics for mental disorders such as autism.”


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