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

Source: Medical University of South Carolina

A cross-disciplinary team of researchers at the Medical University of South Carolina (MUSC) College of Medicine discovered hearing loss in preclinical autism spectrum disorder (ASD).

In particular, the researchers Journal of Neuroscience As soon as you notice a slight hearing loss and defects in the function of the auditory nerve.

A closer look at nerve tissue reveals abnormal support cells called glia, such as aging and inflammation. The findings of this study highlight the importance of considering the senses and their connections to the brain in understanding ASD.

Many patients with ASD have increased sensitivity to sound. While many scientists have previously looked to the brain for the cause, the MUSC team took a different approach by studying the peripheral auditory system.

“Hearing loss can affect the upper auditory system and ultimately cognitive function,” said Hainan Lang, a professor in MUSC’s Department of Pathology and Laboratory Medicine. of the study. Jeffrey Ramschlag, PhD, a postdoctoral researcher in the Hearing Studies Program at MUSC, is co-first author of the manuscript.

Previous studies of age-related hearing loss have shown that the brain can increase its response to reducing auditory signals from the inner ear. Lang wanted to know if this increase in so-called central gain could contribute to the brain’s abnormal response to sound in ASD. However, she faces a major obstacle in her path.

“We didn’t have a clinically relevant model to directly test this important fundamental question,” she said.

The preclinical model that allowed Lang to test her hypothesis was developed by MUSC neuroscience chair Christopher Cowan, Ph.D. The mice in this model have only one working copy of a gene called MEF2C. Cowan’s group had previously studied MEF2C for its role in brain development and found that it is important for regulating the cycle in the brain.

They were particularly interested in creating a preclinical model when a group of ASD-like patients were diagnosed with MEF2C mutations. Cowan’s models also show ASD-like features, including hyperactivity, repetitive behavior, and communication deficits.

Lang and Cowan’s collaboration began when they presented posters side by side at MUSC’s College of Graduate Studies orientation. Lang’s lab identified molecular regulators critical to inner ear development, including MEF2C, and saw Cowan’s model being used to test her hypothesis about hearing loss in neurodevelopmental disorders. Cowan enthusiastically agreed, and the research team began evaluating the hearing ability of MEF2C-deficient mice.

He measured the brain’s response to auditory cues for the first time using a modified version of a test commonly used to screen newborn infants for hearing loss. Mild hearing loss has been reported with only one copy of MEF2C, while hearing loss is common in people with two copies of MEF2C.

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

The researchers used advanced microscopes and staining techniques to determine what caused their vision to go wrong with the auditory nerve. Although the overall hearing loss was mild, the researchers were pleased to see a large difference in auditory nerve response.

The neurons of mice with a single copy of MEF2C showed cellular dysfunction similar to that seen in age-related hearing loss. The researchers also saw signs of increased inflammation in blood vessels and activated immune cells by immune cells called glia and macrophages. This finding was particularly surprising to the researchers.

“Gial cells were not my first thought. I thought it was a nervous breakdown,” Lang said. “We now understand that auditory nerve activity can involve the immune system, and this is a new direction we want to continue our research.”

Cowan believes the discovery will pave the way for a new area of ​​neuroscience research.

This shows the neurons
Expression of MEF2C protein (green) in the nucleus of neuronal cells (stained with red neuronal marker protein) in the inner ear of young adult mice. Nuclei were stained with DAPI (blue). Image courtesy of Dr. Hainan Lang of the Medical University of South Carolina.

“Nowadays, we have a greater appreciation for the important interaction between the immune system in your body and the immune system in the brain,” he said. “The two systems play a critical role in shaping how the cells of the nervous system communicate with each other, in part by pruning out excessive or inappropriate connections that are an important aspect of healthy brain development and function.”

The findings of this study may be useful not only for patients with MEF2C deficiency, but also for people with ASD or hearing loss.

“Understanding how this gene is involved in ear development and how the development of the inner ear affects brain development is very applicable,” Cowan said.

In future studies, the researchers will want to determine exactly how MEF2C causes the changes described in this study. The research team hopes to explore these findings in non-invasive hearing tests for patients with MEF2C deficiency.

Lang and Cowan emphasize the need for collaboration across disciplines to allow such studies to take place.

“The power of collaboration is huge for a place like MUSC,” Cowan said. “This collaboration was a perfect fit for us because Dr. Lang is an auditory and developmental expert, while I’m more of a genetics and molecular developmental person. These types of collaborations are ideal, and it’s something that MUSC is encouraging many of us to think about doing more and more.

“In other words, we each play different instruments so that, together, we can create a better harmony,” Lang said.

About ASD and Hearing Neuroscience Research News

Author: Kimberly McGee
Source: Medical University of South Carolina
Contact: Kimberly McGee – Medical University of South Carolina
Image: Image is credited to Dr. Hainan Lang at the Medical University of South Carolina.

Preliminary study: Closed access.
Peripheral auditory nerve impairment in a mouse model of syndromic autism” by Christopher Cowan et al Journal of Neuroscience


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Peripheral auditory nerve impairment in a mouse model of syndromic autism

Disruption of the function of the peripheral auditory nerve (AN) contributes to dynamic changes in the central auditory system, resulting in abnormal hearing, including hypersensitivity.

Altered sound sensitivity is frequently observed in autism spectrum disorders (ASD), where AN deficits and auditory information processing alterations contribute to SD-related symptoms, including social communication deficits and hyperacusis.

The MEF2C transcription factor is associated with risk for several neurodevelopmental disorders and mutations or deletions. MEF2C Produce haploinsufficiency syndrome characterized by ASD, language and cognitive deficits.

A mouse model of this syndromic ASD (Mef2c-het) repeats many of them MEF2C Features associated with haploinsufficiency syndrome, including connectivity defects. We show here that it is. Mef2c– Het mice of both sexes show functional impairment of peripheral AN and moderate hearing loss.

We find that MEF2C is expressed in several AN and cochlear cell types during development; And in Mef2c-Het mice, we observe several cellular and molecular changes associated with AN, including abnormal myelination, neuronal degeneration, neuronal mitochondria disorder, and macrophage activation and cochlear inflammation.

These results demonstrate the importance of MEF2C function in inner ear development and function and the involvement of immune cells and other non-neuronal cells. ASD-related phenotypes.

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

A significant statement

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

We have identified several underlying cellular, subcellular, and molecular abnormalities that contribute to persistent AN impairment.

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

The methodological significance of the study is to establish a comprehensive approach to assess peripheral AN function and peripheral AN deficits in mild hearing loss.

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