Beyond the Brain: The Link Between Hearing Loss and Autism Spectrum Disorder

An interdisciplinary research team at 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 in the journal Neuroscience they observed mild hearing loss and deficits
in auditory nerve function.
Further examination of the nerve tissue reveals abnormal support cell glia, age-like degeneration, and inflammation
.
The results of this study highlight the importance of
considering sensory organs and their interactions with the brain when understanding ASD.

Many people with ASD show increased
sensitivity to sound.
While many scientists have studied the underlying causes of the brain in the past, the MUSC team took a different approach
by studying the peripheral hearing system.

"Hearing impairment may have effects on the higher auditory system and ultimately cognitive function," said Hainan Lang, MD, a professor in the Department of Pathology and Laboratory Medicine at MUSC and one of
the study's two senior authors.
Dr.
Jeffrey Rumschlag, a postdoctoral researcher in the MUSC Hearing Research Project, is co-first author
of the manuscript.

Previous studies of age-related hearing loss have shown that the brain can increase its response to compensate for the decrease
in auditory signals from the inner ear.
Lang wanted to find out whether this increase, known as central gain, causes abnormal brain responses
to sounds in people with autism spectrum disorder.
However, there was a major obstacle
in her path.

"We don'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
in the lab of Dr.
Christopher Cowen, chair of neuroscience at MUSC.
Mice in this model have only one working copy of
the MEF2C gene.
Cowan's group has previously studied the role of MEF2C in brain development and found it important
for regulating the formation of brain circuits.
When a group of patients with asd-like symptoms were identified as having a MEF2C mutation, they were particularly interested in
creating preclinical models.
Cowen's model also showed autism-like behaviors, including increased activity, repetitive behaviors, and communication disorders
.

Lang and Cowen's collaboration began with their side-by-side presentation of posters at the orientation of the Graduate School of Nanjing University of
Science and Technology.
Lang's lab has identified molecular regulators, including MEF2C, which are critical for inner ear development, and she thinks Cowen's model could be used to test her hypothesis
that neurodevelopmental disorders cause hearing loss.
Cowan enthusiastically agreed, and the team began assessing the hearing ability
of MEF2C-deficient mice.

They first measured the brain's response to auditory signals, using an improved 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, while hearing remained normal
in mice with two working copies of MEF2C.
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 that mice with only one copy of MEF2C had reduced this neural activity
.

The researchers set their sights on the auditory nerve, and they used advanced microscopy and staining techniques to determine what went wrong
.
Although the overall decline in hearing sensitivity was slight, the researchers were excited to see a huge difference
in auditory neural responses.
Mouse nerves with only one copy of MEF2C showed cell degeneration
similar to age-related hearing loss.
The researchers also found signs of increased inflammation, blood vessels being destroyed and immune cells called glial cells and macrophages activated
.
This finding particularly surprised
the researchers.

"Glial cells weren't what I first thought of; I think it's a change
in neurons.
"Now that we know that auditory neural activity can also involve the immune system, this is a beautiful new direction
that we want to continue to study.
"

Cowan also believes that the discovery opens the way
for a new field of neuroscience research.

"We now have a better understanding of the important interactions
between the human immune system and the brain's immune system," he said.
"These two systems play a key role in shaping how nervous system cells communicate with each other, in part by pruning the excessive or inappropriate connections that have been formed, which is an important aspect of
healthy brain development and function.
"

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

"There is tremendous applicability to understanding how this gene is involved in ear development, and how inner ear development affects brain development
," Cowan said.

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

Both Lang and Cowan emphasized the importance of interdisciplinary collaboration to enable such research to be conducted
.

"For a place like MUSC, the power of collaboration is huge," Cowan said
.
"This collaboration is ideal for us because Dr.
Lang is an expert in hearing function and development, and I am more of an expert
in genetics and molecular development.
This type of collaboration is ideal, and that's exactly what MUSC encourages many of us to think about doing more
.
”

"In other words, each of us plays a different instrument, so together we can create better harmony
.
"