UB researchers discover how a high-level risk gene for autism spectrum disorder causes seizures – archyde

Mon, 22.11.2021 12:00 o’clock

Researchers also identify a possible treatment strategy

From the university in Buffalo

Researchers at the University at Buffalo have revealed the biological mechanisms behind an important risk gene that plays a role in a number of brain diseases, including autism spectrum disorder (ASD). They have also discovered a method to potentially salvage some of the comorbidities that this risk gene causes.

Preclinical research published in Nature Communications focuses on a gene called ASH1L. Large-scale human genetic studies have identified ASH1L as a high-risk gene for ASD and sometimes associated conditions such as epilepsy, Tourette’s syndrome, and intellectual disability.

But how exactly the loss of function of ASH1L contributes to all these diseases with overlapping symptoms has remained largely unknown.

Led by Zhen Yan, Ph.D., senior author and SUNY Distinguished Professor in the Department of Physiology and Biophysics of the Jacobs School of Medicine and Biomedical Sciences at the UB, the team was motivated to conduct the study after it was initially discovered found that ASH1L expression is significantly reduced in the prefrontal cortex (PFC) of post-mortem tissue from ASA patients. The prefrontal cortex is the part of the brain responsible for executive functions such as cognitive processes and emotional control.

The UB researchers found that in mice with ASH1L deficiency in the PFC, synaptic genes, which are responsible for proper information processing in the brain, are downregulated. This causes an imbalance in the signals transmitted by the most important excitatory and inhibitory neurotransmitters in the nervous system: glutamate or gamma-aminobutyric acid (GABA). Normal brain function depends on the precise regulation of glutamate and GABA levels in the brain.

At the same time, these mice showed hyperexcitability of glutamatergic neurons in the prefrontal cortex, which caused severe seizures and early mortality.

Using an approach known as chemogenetic, the UB researchers were able to restore the excitation / inhibition balance between the neurons, reduce seizures and extend the survival of mice with ASH1L deficiency.

However, they found that the social deficits and repetitive behaviors persist in these animals. They plan to investigate other methods that could help overcome these negative effects.

“These results have shown the critical role of a high-level risk factor for autism spectrum disorder in the regulation of synaptic gene expression and seizures, providing insight into treatment strategies for related brain disorders,” said Yan.

In addition to Yan and first author Luye Qin, Ph.D., other co-authors are Jamal B. Williams; Tao Tan, Ph.D .; Tiaotiao Liu, Ph.D .; Qing Cao, Ph.D .; and Kaijie Ma. All are past or current researchers in the Physiology and Biophysics Department of the Jacobs School.

Funding was provided by the National Institutes of Health and the Nancy Lurie Marks Family Foundation.


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