overview: MEF2C, a gene important for regulating brain development and circuit formation within the brain, also plays an important role in inner ear development. Mutations in MEF2C were previously associated with he ASD. Researchers found that mice with only one copy of the MEF2C gene had reduced activity in the auditory nerve.
sauce: Medical College of South Carolina
A multidisciplinary team of researchers from the medical school of the Medical University of South Carolina (MUSC) discovered hearing impairment in a preclinical model of autism spectrum disorder (ASD).
More specifically, researchers Journal of Neuroscience They observed mild deafness and auditory nerve function deficits.
Closer examination of nerve tissue revealed abnormal support cells called glia, senescence-like degeneration, and inflammation. The results of this study highlight the importance of considering sensory-brain interactions in understanding ASD.
Many people with ASD have an increased sensitivity to sound. While many scientists have focused on the brain for underlying causes, the MUSC team took a different approach by studying the peripheral auditory system.
“Hearing impairment can affect higher auditory systems and ultimately cognitive function,” says Professor of Pathology and Laboratory Medicine at MUSC and one of two senior authors. According to Hainan Lang, MD, Ph.D. of research. Dr. Jeffrey Rumschlag, a postdoctoral fellow in the MUSC Hearing Research Program, is the co-first author of this manuscript.
Previous studies on age-related hearing loss have shown that the brain can increase its response to compensate for the loss of auditory signals from the inner ear. Lang wanted to investigate whether this increase, called central gain, contributed to the abnormal brain responses to sounds in ASD.
“There were no clinically relevant models to directly test this important underlying problem,” she said.
The preclinical model that allowed Lang to test the hypothesis was developed in the lab of Dr. Christopher Cowan, chair of MUSC’s Neuroscience Division. Mice in this model have only one working copy of a gene called MEF2C. Cowan’s group has previously studied the role of his MEF2C in brain development and found it to be important in regulating circuit formation within the brain.
They became particularly interested in creating preclinical models when a group of patients with ASD-like symptoms were identified with MEF2C mutations. Cowan’s model also shows ASD-like behaviors such as increased activity, repetitive behaviors, and impaired communication.
Lang and Cowan’s collaboration began when they presented side-by-side posters at the orientation of MUSC’s College of Graduate Studies. Lang’s lab has identified key molecular regulators of inner ear development, including MEF2C, and sees Cowan’s model as one that could be used to test her hypothesis of hearing loss in neurodevelopmental diseases. I was. Cowan enthusiastically agreed, and the research team began evaluating hearing in her MEF2C-deficient mice.
They first measured the brain’s response to auditory signals using a modified version of a test commonly used to screen newborns for hearing loss. Mild hearing loss was observed in mice with only one working copy of MEF2C, whereas hearing remained normal in mice with two working copies.
To further investigate this loss, researchers measured activity in the auditory nerve, which carries signals from the inner ear to the brain. They found that mice with only one copy of MEF2C had reduced activity in this neuron.
Researchers zeroed in on the auditory nerve and used advanced microscopy and staining techniques to pinpoint what was wrong. Although the reduction in overall auditory sensitivity was mild, the researchers were excited by the significant difference in how the auditory nerve responded.
Neurons from mice with a single copy of MEF2C exhibited cell degeneration that mimics that seen in age-related hearing loss. The researchers also saw signs of increased inflammation, such as blood vessels being destroyed and immune cells called glia and macrophages being activated. This discovery was particularly surprising to researchers.
“Glial cells weren’t my first thought. I thought they were neuronal changes,” Lang said. “Now we know that the activity of the auditory nerve may also be involved in the immune system. It’s a beautiful new direction that we want to continue our research.”
Cowan also believes the discovery will pave the way for new areas of neuroscience research.
“We have a better understanding of the important interactions between the body’s immune system and the immune system in the brain,” he said. “These two systems play a key role in shaping the way nervous system cells communicate with each other, in part by pruning the excess or inappropriate connections that have formed. This is an essential aspect of healthy brain development and function.”
The findings from this study may be important not only for patients with MEF2C deficiency, but also for ASD and hearing loss in general.
“Understanding how this gene is involved in ear development and how inner ear development influences brain development is highly applicable,” Cowan said. increase.
In future studies, researchers aim to discover exactly how MEF2C triggers the changes identified in this study. The research team also hopes to investigate these findings in patients with MEF2C deficiency using non-invasive audiometry.
Both Lang and Cowan emphasize the importance of cross-disciplinary collaboration to enable such research.
“The power of collaboration is tremendous for a place like MUSC,” says Cowan. Dr. Lang is an expert in auditory function and development, and I am an expert in genetics and molecular development, so this collaboration was ideal for us. is what prompts us to think more. ”
“In other words, we each play a different instrument, so together we can create better harmonies,” Lang said.
About this ASD and auditory neuroscience research news
author: Kimberly McGee
sauce: Medical College of South Carolina
contact: Kimberly McGee – Medical College of South Carolina
image: Image credited to Dr. Hainan Lang, Medical College of South Carolina.
Original research: closed access.
“Peripheral auditory neuropathy in a mouse model of symptomatic autism” by Christopher Cowan et al. Journal of Neuroscience
overview
See also
Peripheral auditory neuropathy in a mouse model of symptomatic 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 sensitivity to sound is frequently observed in autism spectrum disorders (ASD), and AN impairment and alterations in auditory information processing may contribute to ASD-associated symptoms such as impaired social communication and hyperacusis. suggests that
The MEF2C transcription factor is associated with risk of several neurodevelopmental disorders and mutations or deletions. MEF2C It causes a haploinsufficiency syndrome characterized by ASD, language, and cognitive deficits.
This mouse model of symptomatic ASD (Mef2c-Het) is MEF2C Behaviors associated with haploinsufficiency syndrome, including communication disorders.show it here Mef2c– Male and female Het mice show peripheral AN dysfunction and slightly reduced auditory sensitivity.
MEF2C was found to be expressed during development in multiple AN and cochlear cell types.and Mef2cMultiple cellular and molecular alterations associated with AN are observed in -Het mice, including abnormal myelination, neuronal degeneration, neuronal mitochondrial dysfunction, increased macrophage activation and cochlear inflammation.
These results reveal the importance of MEF2C function 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 directly or indirectly may contribute to AN dysfunction. ASD-associated phenotype.
Finally, our study establishes a comprehensive approach to characterize AN function at the physiological, cellular, and molecular levels in mice. It is applicable to animal models with a wide range of human auditory processing deficits.
Explanation of important matters
This is the first report of peripheral auditory nerve (AN) injury in a human mouse model. MEF2C A haploinsufficiency syndrome that presents well-characterized ASD-associated behaviors, including communication deficits, hyperactivity, repetitive behaviors, and social impairment.
We identify multiple underlying cellular, intracellular and molecular abnormalities that may contribute to peripheral AN disorders.
Our findings also highlight the critical role of immune cells (such as cochlear macrophages) and other non-neural elements (such as glial cells and cells of the stria vascularis) in hearing impairment in ASD.
The methodological significance of this study is the establishment of a comprehensive approach to assess peripheral AN function and the effects of peripheral AN disorders with minimal hearing loss.
