A link between hearing loss and autism spectrum disorder

Resume: MEF2C, a gene critical for brain development and the formation of regulatory circuits in the brain, also plays an important role in the development of the inner ear. MEF2C mutations have previously been linked to ASD. The researchers found that mice with only one copy of the MEF2C gene had reduced activity in the auditory nerve.

Fountain: Medical University of South Carolina

An interdisciplinary team of researchers from the Medical University of South Carolina (MUSC) School of Medicine discovered hearing impairment in a preclinical model of autism spectrum disorder (ASD).

More specifically, the researchers report in the neuroscience journal who noted mild hearing loss and defects in auditory nerve function.

Closer examination of the nerve tissue revealed abnormal support cells called glia, degeneration and inflammation similar to aging. The findings of this study highlight the importance of considering the sensory organs and their interactions with the brain in understanding ASD.

Many patients with ASD show increased sensitivity to sound. While many scientists in the past looked to the brain for an underlying cause, the MUSC team took a different approach when studying the peripheral auditory system.

“Hearing impairment can have an impact on the higher-level auditory system and eventually cognitive function,” said Hainan Lang, MD, Ph.D., a professor in the Department of Pathology and Laboratory Medicine at MUSC and a of the two main authors. of the studio. Jeffrey Rumschlag, Ph.D., a postdoctoral researcher in the MUSC Hearing Research Program, is a co-author of the manuscript.

Previous studies of age-related hearing loss have shown that the brain can increase its response to compensate for reduced auditory signals from the inner ear. Lang wanted to find out if this increase, called central gain, might contribute to an abnormal brain response to sound in ASDs. However, a major obstacle stood in his way.

“We did not have a clinically relevant model to directly test this important fundamental question,” he said.

The preclinical model that would allow Lang to test his hypothesis was developed in the lab of Christopher Cowan, Ph.D., chair of Neuroscience at MUSC. Mice in this model have only one working copy of a gene called MEF2C. Cowan’s group had studied MEF2C in the past for its role in brain development and found that it was important in regulating the formation of circuits in the brain.

They became especially interested in creating a preclinical model when MEF2C mutations were identified in a group of patients with ASD-like symptoms. Cowan’s models also show behaviors similar to those of ASD, including increased activity, repetitive behavior, and communication deficits.

Lang and Cowan’s collaboration began when they presented posters side by side at an orientation to the College of Graduate Studies at MUSC. Lang’s lab had identified molecular regulators, including MEF2C, crucial for inner ear development, and he saw Cowan’s model as something he could use to test his hypotheses about hearing loss in neurodevelopmental diseases. Cowan enthusiastically agreed, and the research team began evaluating the hearing ability of the MEF2C-deficient mice.

They first measured the brain’s response to auditory cues, using a modified version of a test commonly used to assess newborn hearing loss. Mild hearing loss was observed in mice with only one working copy of MEF2C, while hearing remained normal in those with two working copies.

To further investigate this loss, the researchers measured the activity of the auditory nerve, which carries signals from the inner ear to the brain. They found reduced activity in this nerve in mice with only one copy of MEF2C.

With an eye on the auditory nerve, the researchers used advanced microscopes and staining techniques to determine what was wrong. Although the overall loss of hearing sensitivity was mild, the researchers were excited to see a big difference in auditory nerve response.

Nerves from mice with a single copy of MEF2C showed cell degeneration very similar to that seen in age-related hearing loss. The researchers also saw signs of increased inflammation, with ruptured blood vessels and activated immune cells called glia and macrophages. This finding was especially surprising to the researchers.

“Glial cells were not my first thought; I thought it was a neural change,” Lang said. “We now understand that auditory nerve activity may also involve the immune system, and that’s a beautiful new direction that we want to continue to explore.”

Cowan also believes the finding opens the way for a new area of ​​research in neuroscience.

This shows the neural cells
Expression of the MEF2C protein (green) in neuronal cell nuclei (stained with a neuronal marker protein in red) in the inner ear of a young adult mouse. Nuclei were stained with Dapi (blue). Image courtesy of Dr. Hainan Lang of the Medical University of South Carolina.

“We now appreciate more that there is an important interaction between the immune system in your body and the immune system in your brain,” he said. “The two systems play critical roles in shaping how cells in the nervous system communicate with each other, in part, by removing excessive or inappropriate connections that have been formed, and this is an essential aspect of healthy development and function. of the brain”.

The findings of this study could be important not only for patients with MEF2C deficiency, but also for people with ASD or hearing loss in general.

“Understanding how this gene may be involved in ear development and how inner ear development is affecting brain development has great applicability,” Cowan said.

In future studies, the researchers aim to discover how exactly MEF2C causes the changes that were identified in this study. The research team also hopes to explore these findings in patients with MEF2C deficiency using non-invasive hearing tests.

Lang and Cowan emphasize the importance of cross-disciplinary collaboration in enabling studies like this to take place.

“The power of collaboration is tremendous for a place like MUSC,” Cowan said. “This collaboration, for us, was ideal because Dr. Lang is an expert in hearing function and development, whereas I am more of a genetics and molecular development person. These types of collaborations are ideal, and it is precisely what MUSC encourages many of us to think about doing more and more.

“In other words, each of us plays different instruments so that together we can make better harmony,” Lang said.

About this research news on ASD and auditory neuroscience

Author: Kimberly McGhee
Fountain: Medical University of South Carolina
Contact: Kimberly McGhee – Medical University of South Carolina
Picture: Image is credited to Dr. Hainan Lang, Medical University of South Carolina

original research: closed access.
Peripheral auditory nerve impairment in a mouse model of syndromic autism” by Christopher Cowan et al. neuroscience journal


See also

This shows people holding hands.

Peripheral auditory nerve impairment in a mouse model of syndromic autism

Peripheral auditory nerve (PA) dysfunction contributes to dynamic changes throughout the central auditory system, resulting in abnormal auditory processing, including hypersensitivity.

Impaired sound sensitivity is frequently seen in autism spectrum disorder (ASD), suggesting that AN deficits and changes in auditory information processing may contribute to symptoms associated with ASDs, including deficits. of social communication and hyperacusis.

The transcription factor MEF2C is associated with the risk of several neurodevelopmental disorders and mutations or deletions of MEF2C produce a haploinsufficiency syndrome characterized by autism spectrum, language and cognitive disorders.

A mouse model of this syndromic ASD (mef2c-Het) recapitulates many of the MEF2C behaviors related to haploinsufficiency syndrome, including communication deficits. We show here that mef2c-Het mice of both sexes exhibit functional impairment of peripheral AN and a modest reduction in hearing sensitivity.

We found that MEF2C is expressed during development in multiple AN and cochlear cell types; and in mef2c-In Het mice, we observed multiple cellular and molecular alterations associated with AN, including abnormal myelination, neuronal degeneration, neuronal mitochondria dysfunction, and increased macrophage activation and cochlear inflammation.

These results reveal the importance of MEF2C function in the development and function of the inner ear and the commitment of immune cells and other non-neuronal cells, suggesting that microglia/macrophages and other non-neuronal cells could contribute, directly or indirectly. , to AN dysfunction and ASD-related phenotypes.

Finally, our study establishes a comprehensive approach to characterize AN function at the physiological, cellular, and molecular levels in mice, which can be applied to animal models with a wide range of human auditory processing impairments.


This is the first report of peripheral auditory (AN) nerve impairment in a mouse model of human. MEF2C Haploinsufficiency syndrome that has well-characterized ASD-related behaviors, including communication deficits, hyperactivity, repetitive behavior, and social deficits.

We identified multiple underlying cellular, subcellular, and molecular abnormalities that may contribute to the impairment of peripheral AN.

Our findings also highlight the important roles of immune cells (eg, cochlear macrophages) and other non-neuronal elements (eg, glial cells and cells in the stria vascularis) in hearing impairment in ASDs.

The methodological importance of the study is the establishment of a comprehensive approach to assess peripheral AN function and the impact of peripheral AN deficits with minimal hearing loss.

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