ATP-Purinergic Mechanisms Underlying Noise-Induced Cochlear Synaptopathy and Hearing Loss

ATP-purinergic mechanisms underlying noise-induced cochlear synaptopathy and hearing loss Summary Noise is a common risk-factor for hearing loss. Recent studies demonstrated that noise can induce spiral ganglion (SG) neuron degeneration even without apparent hair cell loss. In particular, low spontaneous rate (LSR) auditory nerves (ANs) and their synaptic connections with inner hair cells (IHCs) are preferentially lost leading to hidden hearing loss. However, the underlying mechanisms remain unclear. It is well-known that afferent auditory nerve fibers emanating from each IHC have different spontaneous rates (SRs) and electrophysiological response properties. This indicates that different responding properties of LSR and high-SR (HSR) fibers are not determined by connected IHCs, and also suggests that substances other than primary neurotransmitter glutamate also play some roles in synaptic transmission and the regulation of AN activity. ATP-purinergic (P2) receptors have been found to play such function in other neuron systems. ATP receptors of P2X and P2Y subtypes also have extensive expression in the cochlea, including SG neurons. In the cochlea, it has been long-term determined that ATP plays important roles in a wide range of physiological and pathological processes. In particular, our previous study demonstrated that ATP-P2X receptors are required for K+-sinking in the cochlea. ATP also can suppress HSR fiber firing. Recently, we found that P2X2 mutations can induce nonsyndromic hearing loss and increase susceptibility to noise stress, further indicating that ATP-purinergic signaling has a critical role in noise-induced hearing loss. We hypothesize that ATP-P2 receptors may have a critical role in IHC-AN synaptic transmission; LSR and HSR SG fibers may have different P2 receptor expressions, thereby resulting into different response properties and susceptibilities to noise. In this project, we will first identify and characterize P2 receptor expression in SG neurons, in particular, at LSR and HSR fiber synaptic regions beneath hair cells (Specific Aim 1, SA1). Then, we will test whether deficiency of ATP-purinergic receptors can increase susceptibility to noise causing cochlear synaptopathy (SA2). In SA3, we will further test whether defect of ATP-P2 receptor function can compromise K+-sinking, thereby leading to K+-toxicity and synaptic degeneration. Undoubtedly, completion of these studies will reveal molecular mechanism underlying noise-induced cochlear synaptic degeneration and provide a big advance in our understanding noise-induced hearing loss. These novel studies will also open a new therapeutic avenue for targeting noise induced hearing loss.