During a talk at Loyola University, Dr. Yu presented his current research on the auditory system. Dr. Yu’s research focuses mainly around the cochlea and the cochlear nucleus. During the talk, Dr. Yu mentioned how the auditory information is transmitted from structure to structure. The neurons that are responsible for transmitting the auditory information from the inner ear to the brain are the spiral ganglion neurons. The spiral ganglion neurons have peripheral fibers and central fibers. The peripheral fibers will extend to the cochlea and innervate the hair cells. The central fibers of the spiral ganglion neurons will form the auditory nerve and it will innervate the auditory brainstem. After the auditory nerve has entered the brainstem, it will split and will innervate three distinct regions of the cochlear nucleus. The descending branch will innervate both the dorsal cochlear nucleus and the posteroventral cochlear nucleus. The other branch named the ascending branch will innervate the anterior ventral cochlear nucleus. The sound information will further be sent from the cochlear nucleus to other structures such as the midbrain, thalamus, and cortex.
It was also stated that there is a tonotopic map present in the auditory system. The spiral ganglion neuron cell bodies and the nerve fibers are positioned along the cochlea in respect to their frequency sensitivity. The spiral ganglion neurons that usually respond to high frequencies are located at the base of the cochlea and the spiral ganglion neurons that respond to low frequencies are located at the apex of the cochlea. There is also a tonotopic arrangement in the cochlear nucleus. The spiral ganglion neurons present at the base of the cochlea will send their fibers to the dorsal part of the cochlear nucleus and the spiral ganglion neurons located at the apex will project their fibers to the ventral part of the cochlear nucleus.
There is a plenty of information on the tonotopic map, but what is poorly understood is the cellular and molecular mechanisms that are responsible for the formation of the tonotopic map.
The inner hair cells which are located in the Organ of Corti are responsible for sensory transduction. The hair cells will convert the mechanical energy that is associated with the traveling sound waves to an electrical signal. When the stereocilia of the hair cells are displaced in the correct direction, it will stretch the tip linkers, and this will open the cation channels present, and this will result in a graded receptor potential which will depolarize the hair cell. The graded receptor potential will result in the opening of voltage gate calcium channels and there will be an influx of calcium. In response to the influx of calcium, the neurotransmitter glutamate will be released, and this will result in an action potential in the peripheral fibers of the spiral ganglion neurons.
The ability for the inner hair cell to be able to recognize the influx of calcium is crucial for the release of glutamate and if the inner hair cell can’t recognize the influx of calcium then it could be detrimental to the relay of sound information.
A study titled, “Dual AAV-mediated gene therapy restores hearing in a DFNB9 mouse model”, wanted to see whether it was possible to reverse or prevent deafness in a mutant mouse model that had a mutation in the otoferlin gene which encodes for the otoferlin protein, which acts as a calcium sensor in the inner hair cells. The otoferlin protein plays a crucial role in the synaptic exocytosis of the neurotransmitter glutamate. If the mouse has a mutation in the otoferlin gene that encodes for the otoferlin protein then it will be deaf due to a problem of failed sound evoked neurotransmitter release at the synapse between the inner hair cell and the peripheral fiber of the spiral ganglion neuron. These otoferlin mutant mice possess a normal sensory epithelium, but they have a mutation in the otoferlin encoding gene and this results in a problem for the release of glutamate from the inner hair cell.
The study that was conducted aimed to see whether gene mediated therapy would be able to reverse or prevent deafness in otoferlin mutant mice. The gene mediated therapy consisted of using Adeno Associated Virus to reinsert a functional otoferlin gene into the mutant otoferlin mice. Adeno Associated Virus is known to be nonpathogenic and it is also known to not cause a harmful immune response, which means that the cells that the virus is affecting won’t be targeted by the immune system. The virus was injected on a different day for different groups. One group of otoferlin mutant mice received the injection on postnatal day 10, which occurs before hearing onset. Hearing onset occurs on postnatal day 12. The other two otoferlin mutant mice groups received the virus injection after hearing onset typically occurs. They received the injection either on postnatal day 17 or postnatal day 30.
The study wanted to figure out whether gene mediated therapy on postnatal day 10 could prevent deafness from occurring in an otoferlin mutant mouse model and whether gene mediated therapy on postnatal day 17 or postnatal day 30 could reverse deafness in an otoferlin mutant mouse model.
The study incorporated auditory brainstem response measurements.ABRs are used to test the hearing threshold and it is also used to analyze the functionality of the auditory pathway. Wave I will tell the researchers if there was a response in the spiral ganglion neurons. The amplitude of the wave tells us how strong the sound stimulus was perceived to be, and latency tells us about the time it took from the presentation of the auditory stimulus to get the first response in the spiral ganglion neurons. It is important to note that if there is a problem with wave I then we will also observe altered waves from then on. If wave I does not exist, then the rest of the waves will not exist.
A few weeks after the virus injection on postnatal day 10, auditory brain response recordings were conducted for the otoferlin mutant mice. These mice displayed a strong restoration in auditory thresholds when presented with either click or tone burst stimuli. The auditory brain stem response thresholds that were observed were similar to those observed in the wild type mice. The researchers also wanted to test out the long-term effects of the gene therapy and they observed many weeks later that the auditory brain stem response threshold was not significantly different from the auditory brain stem responses of the wild type mice.
They did notice a problem with the wave I amplitude of the auditory brainstem response recordings. The amplitude of wave I in the mice that received the gene therapy on postnatal day 10 was half the amplitude of wave I in the wild type mice. It is not exactly known why this occurs, but they did speculate that it somehow had to involve the low number of pre-synaptic ribbon proteins observed.
The study wanted to figure out whether gene mediated therapy on postnatal day 10 could prevent deafness from occurring in an otoferlin mutant mouse model and whether gene mediated therapy on postnatal day 17 or postnatal day 30 could reverse deafness in an otoferlin mutant mouse model.
The study incorporated auditory brainstem response measurements.ABRs are used to test the hearing threshold and it is also used to analyze the functionality of the auditory pathway. Wave I will tell the researchers if there was a response in the spiral ganglion neurons. The amplitude of the wave tells us how strong the sound stimulus was perceived to be, and latency tells us about the time it took from the presentation of the auditory stimulus to get the first response in the spiral ganglion neurons. It is important to note that if there is a problem with wave I then we will also observe altered waves from then on. If wave I does not exist, then the rest of the waves will not exist.
A few weeks after the virus injection on postnatal day 10, auditory brain response recordings were conducted for the otoferlin mutant mice. These mice displayed a strong restoration in auditory thresholds when presented with either click or tone burst stimuli. The auditory brain stem response thresholds that were observed were similar to those observed in the wild type mice. The researchers also wanted to test out the long-term effects of the gene therapy and they observed many weeks later that the auditory brain stem response threshold was not significantly different from the auditory brain stem responses of the wild type mice.
They did notice a problem with the wave I amplitude of the auditory brainstem response recordings. The amplitude of wave I in the mice that received the gene therapy on postnatal day 10 was half the amplitude of wave I in the wild type mice. It is not exactly known why this occurs, but they did speculate that it somehow had to involve the low number of pre-synaptic ribbon proteins observed.
After a few weeks following the injection of the Adeno Associated Virus on either postnatal day 17 or postnatal day 30, researchers conducted Auditory Brainstem Response recordings. They found that the group of otoferlin mutant mice receiving the virus injection on postnatal day 17 displayed hearing recovery. Their auditory brainstem response threshold in response to a click or tone burst stimuli was similar to the ABR threshold in wild type mice. They tested for the long-term effects of the gene therapy and they found a sustained threshold for the mice receiving the injection on postnatal day 17. Once again, they did observe that the wave I amplitude of otoferlin mutant mice receiving the injection on postnatal day 17 was half the amplitude of wave I for the wild type mice.
It is noted that the otoferlin mutant mice receiving the Adeno Associated Virus injection on postnatal day 30 displayed a similar recovery to what was displayed by the otoferlin mutant mice receiving an injection on postnatal day 17.
Overall, this study showed that gene mediated therapy in mutant mice that have a mutation in the otoferlin encoding gene can both prevent deafness from occurring or reverse the deafness. The gene mediated therapy before hearing onset can prevent deafness from occurring and the gene therapy which occurs after the onset of hearing can serve as a method to reverse deafness.
For the future directions of the study, I suggest furthering the study on why is it that when the researchers conducted auditory brainstem response recordings in mice in response to an auditory stimulus, the amplitude of wave I of the mice that received the gene therapy remains half the amplitude of wave I of wild type mice.
It is noted that the otoferlin mutant mice receiving the Adeno Associated Virus injection on postnatal day 30 displayed a similar recovery to what was displayed by the otoferlin mutant mice receiving an injection on postnatal day 17.
Overall, this study showed that gene mediated therapy in mutant mice that have a mutation in the otoferlin encoding gene can both prevent deafness from occurring or reverse the deafness. The gene mediated therapy before hearing onset can prevent deafness from occurring and the gene therapy which occurs after the onset of hearing can serve as a method to reverse deafness.
For the future directions of the study, I suggest furthering the study on why is it that when the researchers conducted auditory brainstem response recordings in mice in response to an auditory stimulus, the amplitude of wave I of the mice that received the gene therapy remains half the amplitude of wave I of wild type mice.
Works Cited
Dual AAV-mediated gene therapy restores hearing in a DFNB9 mouse model
Omar Akil, Frank Dyka, Charlotte Calvet, Alice Emptoz, Ghizlene Lahlou, Sylvie Nouaille, Jacques Boutet de Monvel, Jean-Pierre Hardelin, William W.Hauswirth, Paul Avan, Christine Petit, Saaid Safieddine, Lawrence R. Lustig
Proceedings of the National Academy of Sciences Mar 2019, 116 (10) 4496-4501; DOI:10.1073/pnas.1817537116
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