Regeneration and protection of synapses after noise-induced cochlear synaptopathy

Noise exposure destroys cochlear afferent synapses between inner hair cells and spiral ganglion neurons, even in the absence of hair cell loss or permanent threshold shift. This cochlear “synaptopathy” is a result of excess release of the neurotransmitter glutamate from inner hair cells, and consequent glutamate excitotoxicity. While the focus has typically been on hair cell loss, studies in recent years have identified cochlear synaptopathy as another major contributor to noise- or age-related hearing loss. This noise-induced damage to cochlear synapses or noise-induced synaptopathy is a consequence of excitotoxic trauma to the synapses, that is, entry of Ca2+ to reach toxic intracellular levels because of increased excitation of the synapses in noise. Permanent noise-induced synaptopathy can result from noise even at levels low enough that there is no permanent damage to hair cells. Nevertheless, this reduction of synapses does appear to cause serious hearing impairments, including poor speech comprehension in noisy environments, and even tinnitus. Noise induced cochlear synaptopathy in animal models can be detected as a reduction in the number of synapses on the inner hair cells. Few, if any, synapses normally regenerate, but application of neurotrophic factors such as BDNF or NT-3 promotes regeneration. NT-3 is normally expressed in the organ of Corti, and appears necessary for regeneration. Ciliary Neurotrophic Factor (CNTF) is also normally expressed in the organ of Corti, and we ask here whether CNTF can promote cochlear synapse regeneration after synaptopathy resulting from excitotoxic trauma. Our approach to this issue has been a methodical investigation of the causes of noise-induced synaptopathy and excitotoxicity in the cochlea on the cellular level using combined in vitro and in vivo approaches. These studies have revealed, first, a criticalphysiological cause of synaptopathy and a pharmacological means of blocking it, specifically, a blocker of the neurotransmitter receptor through which Ca2+ ions enter the synapse during excitotoxic trauma; second, and the primary focus, we ask here whether CNTF can promote cochlear synapse regeneration after synaptopathy resulting from excitotoxic trauma; third, that female mice are less susceptible to noise-induced synaptopathy than are males, with susceptibility varying through the estrous cycle.