Neurons in the inner ear were thought to fall into two categories: type 1 and type 2. But scientists from Karolinska Institutet have discovered that type 1 neurons—a heterogeneous group—actually comprise three distinct subtypes of neurons. The findings could help researchers better understand the neurons involved in hearing and support the development of new treatments for hearing loss.
When sound enters the cochlea, or the inner ear, it is converted into electrical signals that are sent to the brain via cochlear neurons. About 95% of these neurons are type 1 and transmit most of the auditory information. The remainder are type 2.
The team used single-cell RNA sequencing to understand the neurons at the molecular level. They identified the smallest group, type 2 neurons, by their expression of the gene Prph. Type 1 neurons were identified by their lack of Prph and expression of Prox1.
With both groups in hand, the scientists looked for new markers that would differentiate the two groups. All three type 1 subtypes—1a, 1b and 1c—expressed not just Prox1 but also Slc17a6 (VGlut1), Trpm2 and Epha4. Each subtype expressed its own unique set of genes in addition to the four genes expressed by all type 1 neurons.
“We now know that there are three different routes into the central auditory system, instead of just one,” said Francois Lallemand, research group leader at the Department of Neuroscience of the Karolinska Institutet, in a statement. “Our study can open the way for the development of genetic tools that can be used for new treatments.” The study appears in Nature Communications.
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The study opens the door to using gene expression as a marker to identify which neuron types are involved in different forms of hearing loss. But genes may be used as a therapeutic target too; as many as half of all cases of deafness are caused by genetic defects.
For example, NIH researchers restored some hearing in mouse models of an inherited type of deafness after pinpointing the exact location of the mutation that caused it. They used small molecules to target a DNA-binding protein that blocked the expression of a gene that is important for hearing. Akouos is using a gene therapy approach to deliver genes to sensory cells in the inner ear and treat certain forms of hearing loss. The company’s first focus is monogenic forms of sensorineural hearing loss, which occur when changes to a single gene lead sensory cells or nerve fibers in the inner ear to malfunction.
The Karolinska Institutet team highlighted hyperacusis, or oversensitivity to sound, as a potential application for their findings. The study suggested that the three type 1 subtypes likely play a role in decoding volume, which is important in hearing disorders such as hyperacusis and tinnitus. “Once we know which neurons cause hyperacusis we’ll be able to start investigating new therapies to protect or repair them,” Lallemand said. “The next step is to show what effect these individual nerve cells have on the auditory system, which can lead to the development of better auditory aids such as cochlear implants.”