Researchers identify pathological mechanism for autism and intellectual disability

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A University of Nebraska Medical Center (UNMC) researcher and his team at the Munroe-Meyer Institute (MMI) have made a breakthrough in finding the mechanism and a possible therapeutic fix for autism and intellectual disability.

Woo-Yang Kim, PhD, associate professor, developmental neuroscience, led a team of researchers from UNMC and Creighton University into a deeper exploration of a genetic mutation that reduces the function of certain neurons in the brain.

Their findings were published in Nature Neuroscience.

This is an exciting development because we have identified the pathological mechanism for a certain type of autism and intellectual disability.

Dr Kim said.

Recent studies have shown that the disorder occurs when a first-time mutation causes only one copy of the human ARID1B gene to remain functional, but it was unknown how it led to abnormal cognitive and social behaviours.

Autism spectrum disorder (ASD) impairs the ability of individuals to communicate and interact with others. About 75 per cent of individuals with ASD also have intellectual disability, which is characterised by significant limitations in cognitive functions and adaptive behaviours.

There are no drugs or genetic treatments to prevent ASD or intellectual disability; the only treatment options focus on behavioural management and educational and physical therapies.

Dr Kim’s team created and analysed a genetically modified mouse and found that a mutated ARIS1B gene impairs GABA neurons, the ‘downer’ neurotransmitter, leading to an imbalance of communication in the brain.

GABA blocks impulses between nerve cells in the brain. Low levels of GABA may be linked to anxiety or mood disorders, epilepsy and chronic pain. It counters glutamate (the upper neurotransmitter), as the two mediate brain activation in a Yin and Yang manner. People take GABA supplements for anxiety.

In normal behavior, the brain is balanced between excitation and inhibition, but when the inhibition is decreased, the balance is broken and the brain becomes more excited causing abnormal behavior.

We showed that cognitive and social deficits induced by an ARID1B mutation in mice are reversed by pharmacological treatment with a GABA receptor modulating drug. And, now we have a designer mouse that can be used for future studies.

Dr Kim said.

Next steps for Dr Kim and his team are to even further refine the specific mechanism for autism and intellectual disability and to identify which of the many GABA neurons are specifically involved.

Dr Kim’s research was supported by a $1.7 million grant from the National Institute of Neurological Disorders and Stroke and a $400,000 Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health.

Team members were: Eui-Man Jung, post-doc research associate, and Channabasavaiah Gurumurthy, PhD, associate professor, MMI; Jeffrey Jay Moffat, graduate research assistant, pharmacology/experimental neuroscience, UNMC; and Shashank Dravid, PhD, associate professor, and Jinxu Liu, pharmacology, Creighton University.

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