How a top-ranking risk gene for autism spectrum disorders causes seizures

How a top-ranking risk gene for autism spectrum disorders causes seizures
Fig. 1: ASH1L expression and H3K4me3 level are significantly decreased in PFC of postmortem ASD patients, which is replicated by knockdown of Ash1L in PFC of young mice. a Quantitative PCR data showing ASH1L mRNA levels in postmortem PFC tissues from control humans vs. idiopathic ASD patients. n = 12 humans (10 M,2 F)/group, **p < 0.01, two-tailed t test. b Western blot data showing H3K4me3 and H3K36me2 levels in postmortem PFC from control vs. ASD patients. n = 12 humans(10 M,2 F)/group, *p < 0.05, two-tailed t test. c Quantitative PCR data showing Ash1L mRNA level in N2A cells transfected with Ash1L shRNA or scrambled (sc) shRNA. n = 6/group. ***p < 0.001, two-tailed t test. d A confocal image showing the viral-infected PFC region (stained with DAPI, blue) from a mouse with the stereotaxic injection of Ash1L shRNA AAV (GFP-tagged). Scale bar: 300 μm. e, f Quantitative PCR and Western blot data showing Ash1L mRNA and protein levels in PFC of mice (5-week-old) with the stereotaxic injection of Ash1L shRNA vs. sc shRNA AAV. Ash1L mRNA, n = 15 mice(8 M,7 F) for sc shRNA group, n = 14 mice(7 M,7 F) for Ash1L shRNA group; Ash1L protein, n = 8 mice(4 M,4 F)/group, ***p < 0.001, two-tailed t test. g Western blot data showing H3K4me3, H3K36me2, and H3K36me3 levels in PFC infected with Ash1L shRNA or scrambled shRNA AAV. n = 8 mice (4 M,4 F)/group, ***p < 0.001, two-tailed t test. h Representative confocal images and quantification of immunostaining of H3K4me3 (red) in PFC neurons infected with Ash1L shRNA or a scrambled shRNA AAV (GFP+ , green). n = 20 images/4 mice (2 M,2 F)/group, ***p < 0.001, two-tailed t test. Scale bar: 10 μm. i, j Representative confocal images and quantification of immunostaining of NeuN (red) and DAPI (blue) in PFC neurons infected with Ash1L shRNA or a scrambled shRNA AAV (GFP+ , green). Slices were collected at 8–9 days postinfection. n = 20 images/4 mice (2 M,2 F)/group. Scale bar: 20 μm. All the full Western blots are included in Supplementary Fig. 7a–c. Data are presented as mean values ± SEM. Detailed statistical data are provided in a Source Data file. Credit: DOI: 10.1038/s41467-021-26972-8

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

The preclinical research, published this week 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.

Led by Zhen Yan, Ph.D., senior author and SUNY Distinguished Professor in the Department of Physiology and Biophysics in the Jacobs School of Medicine and Biomedical Sciences at UB, the team was motivated to do the study after its initial finding that ASH1L expression is significantly decreased in the prefrontal cortex (PFC) of postmortem tissues from ASD patients. The prefrontal cortex is the part of the responsible for executive function, such as cognitive processes and emotional control.

The UB researchers found that in mice with ASH1L deficiency in the PFC, synaptic , 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 , which induced severe seizures and early mortality.

Through an approach they describe as chemogenetic, the UB 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 risk factor in regulating synaptic gene expression and seizures, which provides insights into treatment strategies for related brain diseases," said Yan.

More information: Luye Qin et al, Deficiency of autism risk factor ASH1L in prefrontal cortex induces epigenetic aberrations and seizures, Nature Communications (2021). DOI: 10.1038/s41467-021-26972-8

Journal information: Nature Communications

Citation: How a top-ranking risk gene for autism spectrum disorders causes seizures (2021, November 22) retrieved 30 March 2023 from
This document is subject to copyright. Apart from any fair dealing for the purpose of private study or research, no part may be reproduced without the written permission. The content is provided for information purposes only.

Explore further

Researchers develop first-in-class inhibitors against key leukemia protein


Feedback to editors