A few of the possible treatments for age-related conditions presently under development are essentially enhancement therapies. They compensate in some way for losses incurred over the course of degenerative aging by adding functionality. Some of these treatments, by their nature, can in principle enhance function in young individuals as well. In age-related hearing loss, part of the problem is the loss of sensory hair cells in the inner ear, and part of the problem is the loss of axonal connections between those cells and the brain. What if a therapy could provoke the growth of new axons (and possibly new hair cells), and what if that therapy gave an individual more than the natural number of such connections and sensory cells?
In the course of evaluating NTF3 as a target for axon regrowth, researchers here produce mice lineages that have a greater than usual density of axons connecting sensory hair cells to the brain. These mice can apparently make use of that additional connectivity, and outperform their unmodified peers in tests of hearing that rely upon sensory processing in the brain. It is interesting to speculate as to whether life-long presence of the additional connections is needed in order to develop this improved sensory processing, or whether connections added in adult life would be integrated to incrementally improve sensory processing.
Creating supranormal hearing in mice
Researchers have previously increased the amount of the neurotrophic factor neurotrophin-3 (Ntf3) in the inner ear to promote the recovery of auditory responses in mice that had experienced acoustic trauma, and to improve hearing in middle-aged mice. Here, the researchers altered the expression of the Ntf3 to increase the number of synapses between inner hair cells and neurons. "We knew that providing Ntf3 to the inner ear in young mice increased the number of synapses between inner hair cells and auditory neurons, but we did not know what having more synapses would do to hearing. We now show that animals with extra inner ear synapses have normal thresholds - what an audiologist would define as normal hearing - but they can process the auditory information in supranormal ways."
The mice with increased synapses exhibited enhanced peaks in measured Acoustic Brain Stem response, but also performed better on the Gap-Prepulse Inhibition test, suggesting an ability to process an increased amount of auditory information. "We were surprised to find that when we increased the number of synapses, the brain was able to process the extra auditory information. And those subjects performed better than the control mice in the behavioral test." Hair cell loss had once been believed to be the primary cause of hearing loss in humans as we age. Now, however, it's understood that the loss of inner hair cell synapses can be the first event in the hearing loss process, making therapies that preserve, regenerate and/or increase synapses exciting possible approaches for treating some hearing disorders.
Loss of synapses between spiral ganglion neurons and inner hair cells (IHC synaptopathy) leads to an auditory neuropathy called hidden hearing loss (HHL) characterized by normal auditory thresholds but reduced amplitude of sound-evoked auditory potentials. It has been proposed that synaptopathy and HHL result in poor performance in challenging hearing tasks despite a normal audiogram. However, this has only been tested in animals after exposure to noise or ototoxic drugs, which can cause deficits beyond synaptopathy. Furthermore, the impact of supernumerary synapses on auditory processing has not been evaluated.
Here, we studied mice in which IHC synapse counts were increased or decreased by altering neurotrophin 3 (Ntf3) expression in IHC supporting cells. As we previously showed, postnatal Ntf3 knockdown or overexpression reduces or increases, respectively, IHC synapse density and suprathreshold amplitude of sound-evoked auditory potentials without changing cochlear thresholds. We now show that IHC synapse density does not influence the magnitude of the acoustic startle reflex or its prepulse inhibition. In contrast, gap-prepulse inhibition, a behavioral test for auditory temporal processing, is reduced or enhanced according to Ntf3 expression levels. These results indicate that IHC synaptopathy causes temporal processing deficits predicted in HHL. Furthermore, the improvement in temporal acuity achieved by increasing Ntf3 expression and synapse density suggests a therapeutic strategy for improving hearing in noise for individuals with synaptopathy of various etiologies.
View the full article at FightAging
