Published December 7, 2021
Research in the laboratory of Zhen Yan, PhD, SUNY Distinguished Professor of physiology and biophysics, has revealed the biological mechanisms behind a key risk gene that plays a role in a number of brain diseases, including autism spectrum disorder (ASD).
Yan lab researchers have also discovered a method of potentially rescuing some of the comorbidities that this risk gene causes.
The preclinical research, published in November 2021 in Nature Communications, focuses on a gene known as ASH1L. Large-scale human genetic studies have identified ASH1L as a high-risk gene for ASD, and conditions that sometimes accompany it, such as epilepsy, Tourette syndrome and intellectual disability.
But exactly how the loss of function of ASH1L contributes to all of these diseases with overlapping symptoms has remained largely unknown.
Yan, the senior author, was motivated to do the study after the identified genetic link of ASH1L to ASD. Researchers in her lab found that ASH1L expression is significantly decreased in the prefrontal cortex (PFC) of post-mortem tissues from ASD patients.
The PFC is the part of the brain responsible for executive function, such as cognitive processes and emotional control.
Yan and her team found that in mice with ASH1L deficiency in the PFC, synaptic genes — which are responsible for ensuring proper information processing in the brain — are downregulated.
This causes the imbalance of signals mediated by the major excitatory and inhibitory neurotransmitters in the nervous system: respectively, glutamate and Gamma-aminobutyric acid (GABA). Normal brain functioning depends on precise regulation of glutamate and GABA levels in the brain.
At the same time, these mice demonstrated hyperexcitability of glutamatergic neurons in the PFC, which induced severe seizures and early mortality.
Through an approach they describe as chemogenetic, the researchers were able to restore the excitation/inhibition balance among neurons, reducing seizures and prolonging survival of the mice with ASH1L deficiency.
However, they found that the social deficits and repetitive behaviors in these animals persisted. They plan to continue to study other methods that might result in overcoming these negative effects.
“These results have revealed the critical role of a top-ranking autism spectrum disorder risk factor in regulating synaptic gene expression and seizures, which provides insights into treatment strategies for related brain diseases,” Yan says.
Luye Qin, PhD, a former research assistant professor of physiology and biophysics who completed her postdoctoral training in Yan’s lab in 2021, is first author. Qin is now an assistant professor in the Basic Biomedical Science Department at the University of South Dakota.
Current members of Yan’s lab who are co-authors include:
Other former members of Yan’s lab who are co-authors include:
Funding was provided by the National Institutes of Health and the Nancy Lurie Marks Family Foundation.