The

n e w e ng l a n d j o u r na l

of

m e dic i n e

clinical implications of basic research

Elizabeth G. Phimister, Ph.D., Editor

Restoring Synaptic Connections in the Inner Ear

after Noise Damage
Lisa L. Cunningham, Ph.D., and Debara L. Tucci, M.D.
Fifteen percent of Americans 20 to 69 years of
age have hearing loss caused by exposure to
high levels of noise.1 Noise damage results in
anatomical, physiological, and neurochemical
changes to the auditory system that are thought
to cause functional declines in hearing, tinnitus,
and hyperacusis, all of which can contribute to
difficulty understanding speech, especially in
challenging listening environments.2 Experiments in mice indicate that even moderate noise
exposures can result in permanent loss of synaptic contacts in the inner ear and reduced hearing
function.3 A recent study by Wan and colleagues4
showed that these synaptic connections can be
restored with some help from the surrounding
glia-like supporting cells.
Hearing begins when sound energy initiates
pressure waves in the fluid-filled cochlea. This
fluid movement results in deflection of the actinbased stereocilia bundle that gives the sensory
hair cell its name (Fig. 1). Hair cells are surrounded by supporting cells, which have many
glia-like functions that are reminiscent of both
astrocytes and microglia. Deflection of the stereocilia bundle opens mechanically gated ion channels in the hair-cell membrane, leading to glutamate release at ribbon synapses, which are
unique structures that allow for extremely rapid
multivesicular neurotransmitter release. Glutamate released at ribbon synapses activates receptors on spiral ganglion neurons, which extend axons into the auditory brain stem. Ribbon
synapses are critical for hearing function, and
their loss or dysfunction results in hearing impairment.
The past 5 years have witnessed a transformation in our understanding of the damaging
effects of noise on the inner ear. In 2009, Kujawa
and Liberman3 found that exposure to noise levels that were previously considered to be safe
(i.e., levels that result in temporary changes in

hearing sensitivity from which the ear was

thought to fully recover) actually cause permanent loss of ribbon synapses and changes in
hearing function. This noise-induced synaptopathy (defined as the loss of these synaptic connections) may contribute to hearing impairment in
millions of people, including many who have
normal (or near-normal) hearing sensitivity yet
have difficulty understanding speech in background noise.5 The work of Wan and colleagues
suggests an approach to repair this damage.
The investigators found that overexpression of the
gene encoding neurotrophin 3 (Ntf3) in the glialike supporting cells of the cochlea promotes
the recovery of synapse number and function
after damage caused by noise.4 Ntf3 is a neurotrophin in the nerve growth factor family. It
sustains established neurons and stimulates the
growth of new neurons.
The authors generated conditional mouse
models in which Ntf3 expression was increased
specifically in cochlear supporting cells. They
then exposed the mice to moderately damaging
levels of noise that did not kill hair cells but did
result in synaptopathy both in control mice and
in mice with overexpression of Ntf3 in the supporting cells. Unlike control mice, the mice with
Ntf3 overexpression had recovery of both the
number and function of their ribbon synapses
within 2 weeks. Moreover, when Ntf3 overexpression was not induced until shortly after the
noise damage, it was still effective at restoring
synaptic connections. These data indicate that
noise-induced synaptopathy is reversible, and
they raise the possibility that it could be treated even after exposure to damaging noise an
important consideration for the development of
clinical therapies.
Therapeutic options for persons with noiseinduced hearing loss are currently limited. Hearing aids are beneficial but not perfect (because

n engl j med 372;2nejm.orgjanuary 8, 2015

The New England Journal of Medicine

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181

clinical implications of basic research

Control

Noise damage

Ntf3 expressed in supporting cells

Stereocilia

Ntf3
overexpression

Hair cell
Supporting cell

Ribbon
synapses

Spiral ganglion
neurons

Figure 1. Restoration of Cochlear Synaptic Connections by Ntf3 Overexpression in Supporting Cells.

Hair cells are characterized by an apical stereocilia bundle and multiple basal ribbon synapses that control glutamate release onto spiral ganglion neurons. Hair cells (blue) are surrounded by supporting cells (green) that serve
glia-like functions. Noise damage causes loss of ribbon synapses and diminished hearing function. A recent study by
Wan and colleagues4 showed that the conditional overexpression of Ntf3, which encodes neurotrophin 3, in supporting cells (yellow) in mice resulted in restoration of ribbon synapses after noise damage.

182

they amplify both speech and background noise),

and cochlear implants are suitable only for persons with severe to profound hearing losses who
cannot benefit from hearing aids. The new evidence from the study by Wan and colleagues indicates that the loss of ribbon synapses is reversible in animal models of cochlear synaptopathy
caused by moderately intense noise. The synaptic recovery was limited to the regions of the
cochlea that respond to high-frequency sounds,
and the approach taken in this study probably
will not restore hearing function in persons in
whom the sensory hair cells have died. Nevertheless, if these damaged synaptic connections
can be restored in humans, it could mean improved hearing function for millions of people
who struggle with the damaging effects of noise
exposure.

We thank Dr. Elyssa Monzack for creating an earlier version

of the figure.

Disclosure forms provided by the authors are available with the

full text of this article at NEJM.org.

DOI: 10.1056/NEJMcibr1413201

n engl j med 372;2

From the National Institute on Deafness and Other Communication Disorders, Bethesda, MD (L.L.C.); and the Department
of OtolaryngologyHead and Neck Surgery, Duke University
Medical Center, Durham, NC (D.L.T.).
1. National Institute on Deafness and Other Communication

Disorders. Noise-induced hearing loss (http://www.nidcd.nih.gov/

health/hearing/pages/noise.aspx).
2. Hickox AE, Liberman MC. Is noise-induced cochlear neuropathy key to the generation of hyperacusis or tinnitus? J Neurophysiol 2014;111:552-64.
3. Kujawa SG, Liberman MC. Adding insult to injury: cochlear
nerve degeneration after temporary noise-induced hearing
loss. J Neurosci 2009;29:14077-85.
4. Wan G, Gomez-Casati ME, Gigliello AR, Liberman C, Corfas G.
Neurotrophin-3 regulates ribbon synapse density in the cochlea
and induces synapse regeneration after acoustic trauma. Elife
2014 October 20 (Epub ahead of print).
5. Moser T, Predoehl F, Starr A. Review of hair cell synapse
defects in sensorineural hearing impairment. Otol Neurotol
2013;34:995-1004.
Copyright 2015 Massachusetts Medical Society.

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january 8, 2015

The New England Journal of Medicine

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Copyright 2015 Massachusetts Medical Society. All rights reserved.