A link between hearing loss and autism spectrum disorder Neuroscience News

summary: MEF2C, a gene important for brain development and regulating circuit formation in the brain, also plays an important role in inner ear development. MEF2C mutations have been previously linked to ASD. The 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 multidisciplinary team of researchers at the University of South Carolina Medical School (MUSC) has discovered hearing impairment in a preclinical model of autism spectrum disorder (ASD).

More specifically, the researchers in Journal of Neuroscience They noted mild hearing loss and defects in the function of the auditory nerve.

Close examination of the nerve tissue revealed abnormal supportive cells called glia, degeneration and aging-like inflammation. The results of this study highlight the importance of looking at sensory organs and their interactions with the brain in understanding autism spectrum disorder.

Many ASD patients show an 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 by studying the peripheral hearing system.

“Hearing impairment may have an effect on the higher-level auditory system and, ultimately, on cognitive function,” said Hainan Lang, PhD, professor in the Department of Pathology and Laboratory Medicine at MUSC and one of the study’s lead authors. Jeffrey Romschlag, PhD, a postdoctoral researcher in the MUSC Audiology Research Program, is a co-first author of the manuscript.

Previous studies of hearing loss associated with aging have shown that the brain can increase its response to compensate for decreased auditory signals from the inner ear. Lang wanted to see if this increase, called central gain, could contribute to the brain’s abnormal response to sound in ASD. However, there was a huge hurdle in her way.

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

The preclinical model that would allow Lang to test her hypothesis was developed in the lab of Christopher Cowan, PhD, chair of neuroscience at MUSC. Mice in this model have only one working copy of a gene called MEF2C. Cowan’s team has studied MEF2C in the past for its role in brain development and found that it is important for regulating circuit formation in the brain.

They became particularly interested in establishing a preclinical model when a cohort of patients with autism-like symptoms with MEF2C mutations was identified. Cowan’s models also show autistic-like behaviors, including increased activity, repetitive behavior, and communication deficits.

Lang and Kwan’s collaboration began as they submitted posters alongside an orientation for graduate school at MUSC. Lang’s lab identified molecular regulators, including MEF2C, that are crucial for inner ear development, and saw Cowan’s model as something she could use to test her hypothesis about hearing loss in neurodevelopmental diseases. Cowan enthusiastically agreed, and the research team set about assessing the ability of MEF2C-deficient mice to hear.

They first measured the brain’s response to auditory cues, using a modified version of a test commonly used to screen newborns for hearing loss. Mild hearing impairment 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 transmits signals from the inner ear to the brain. They found reduced activity in this nerve in mice with only one copy of MEF2C.

Focusing on the auditory nerve, the researchers used advanced microscopes and staining techniques to determine what was going wrong. Although the overall hearing sensitivity loss was mild, the researchers were excited to see a significant difference in the auditory nerve response.

Nerves from mice with one copy of MEF2C showed cellular degeneration that closely resembled age-related hearing impairment. The researchers also noted signs of increased inflammation, with blood vessels rupturing and activation of immune cells called glial cells and macrophages. This discovery was particularly surprising to the researchers.

“Glial cells weren’t my first idea; I thought it was a neurological change,” Lang said. “We now understand that auditory nerve activity can also involve the immune system, and this is a beautiful new direction that we want to continue studying.”

Cowan also believes that this discovery opens the way for a new area of ​​neuroscience research.

This indicates neurons
Expression of MEF2C protein (green) in the nuclei of neurons (stained with neuronal marker protein in red) in the inner ear of an adult mouse. Nuclei were stained with Dapi (blue). Image courtesy of Dr. Hainan Lang of the Medical University of South Carolina.

“We now appreciate 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 of the nervous system communicate with each other, in part, by pruning away the excess or inappropriate connections that have formed, and this is a key aspect of proper brain development and function.”

The results of this study could be important not only for patients with MEF2C deficiency but also for people with ASD or hearing loss as a whole.

“Understanding how this gene is involved in ear development and how inner ear development affects brain development has enormous application potential,” Cowan said.

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

Lang and Cowan stress the importance of cross-disciplinary collaboration to allow for studies like this.

“The power of collaboration is huge in a place like MUSC,” Cowan said. “This collaboration, for us, was perfect because Dr. Lange is an expert in hearing function and development, while I am more of a molecular genetics and evolution person. These types of collaborations are ideal, and it’s exactly what MUSC encourages so many of us to consider doing more and more.”

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

About this ASD and auditory neuroscience research news

author: Kimberly McGee
Source: Medical University of South Carolina
communication: Kimberly McGee – Medical University of South Carolina
picture: Image credits to Dr. Hainan Lang, Medical University of South Carolina

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


a summary

See also

This indicates a drugged brain

Peripheral auditory nerve impairment in a mouse model of syndromic autism

Dysfunction of the peripheral auditory nerve (AN) contributes to dynamic changes throughout the central auditory system, resulting in abnormal auditory processing, including hypersensitivity.

Altered sound sensitivity is frequently observed in autism spectrum disorder (ASD), suggesting that neurological deficits and changes in auditory information processing may contribute to autism-related symptoms, including social communication deficits and hyperacusis.

The transcription factor MEF2C is associated with the risk of several neurodevelopmental disorders and mutations or deletions of it MEF2C It produces an individual deficiency syndrome characterized by autism spectrum disorder and language and cognitive deficits.

Mouse model of this ASD syndrome (Mef2c-Het) sums up many MEF2C Behaviors associated with personality deficiency syndrome, including communication deficits. We show that here Mef2cMice of both sexes show peripheral anorexia nervosa dysfunction and a slight decrease in hearing sensitivity.

We found that MEF2C is expressed during development in many cochlear and neurogenic cell types; and in Mef2cIn mice, we observe multiple cellular and molecular changes associated with anorexia nervosa, including abnormal myelogenesis, neuronal degeneration, neuronal mitochondrial dysfunction, increased macrophage activation and cochlear inflammation.

These findings reveal the importance of MEF2C in inner ear development and function, and the involvement of immune cells and other non-neuronal cells, suggesting that microglia/macrophages and other non-neuronal cells may contribute, directly or indirectly, to neuronal dysfunction. and phenotypes associated with autism spectrum disorder.

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

Significance statement

This is the first report of peripheral auditory nerve (AN) impairment in a mouse-to-human model MEF2C Insulin deficiency syndrome characterized by behaviors associated with autism, including communication deficits, hyperactivity, repetitive behavior, and social deficits.

We identify several underlying cellular, sub-cellular, and molecular abnormalities that may contribute to peripheral AN dysfunction.

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 vasculature) in hearing impairment in ASD.

The methodological significance of the study is to establish a comprehensive approach to assess peripheral AN function and the effect of peripheral anorexia nervosa deficits with minimal hearing loss.

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