Deciphering pathophysiological mechanisms of genetic forms of auditory neuropathy – NeuropatHEAR

Auditory deficits are the most frequent sensory defect currently affecting more than 6% of the world population, and, over 700 million people by 2050 expectedly. While hearing impairment is in most cases linked to defective functioning of the auditory sensory hair cells and results in abnormal auditory thresholds, there has been a growing awareness that deficits of the auditory nerve with/without hair cell loss, referred to as auditory neuropathy, may also underlie a substantial proportion of auditory deficits, contributing to at least 10% of the cases of hearing impairment (600.000 patients in France). Moreover, they are difficult to detect because they are often associated with normal auditory thresholds.
Auditory neuropathies encompass a mosaic of congenital and acquired disorders that mostly affect auditory nerve neurons or their synapses, distorting sound information transmitted from the ear to the brain. Despite the severity of associated disabilities (impairment in speech comprehension or sound source localization), auditory neuropathies are poorly understood. Because of their vulnerability, low spontaneous rate (SR) neurons of the auditory nerve, which are involved in the processing of loud sounds, have drawn particular attention. However, our knowledge of the connectivity of low SR neurons, their corresponding central auditory circuits and their associated functions are limited. Through three methodological breakthroughs of the consortium, i) a new non-invasive test called re-emerging auditory brainstem responses, which specifically probes the activity of low SR neurons, ii) the development of a two-photon microscope to image the activity of several auditory nerve neurons simultaneously, and iii) the discovery of two marker genes that each label a population of neurons and are involved in an auditory neuropathy when mutated, NeuropatHEAR aims at deciphering the brain circuits and pathophysiological mechanisms underlying auditory neuropathies.
We will first anatomically and functionally characterize the two auditory nerve neuron populations marked by our two genes of interest using the fate mapping tools we produced. We will then decipher the central auditory circuits activated by these two neuronal populations and their perceptual correlates by combining mRNA detection methods, patch-clamp, in vivo electrophysiology, and behavior paradigms. Finally, we will test the presence of auditory neuropathies in patients carrying mutations for the two rare disease genes we identified using re-emerging auditory brainstem responses in the view of validating this methodology as a new diagnosis tool. By combining mouse and human studies, our consortium will i) make major advancements in understanding the mechanisms underlying auditory neuropathies and ii) address a long-standing controversy regarding the existence of low SR neurons in humans. If validated, reemerging auditory brainstem responses will provide a means to detect auditory neuropathy in patients, considerably speeding up their diagnosis, simplifying their management and avoiding misdiagnosis, a first step necessary in the view of developing therapeutic strategies in the future.