Protection and restoration of cochlear synapses from noise-induced synaptopathy in male and female mice

点击翻译按钮获取中文摘要

Most spiral ganglion neurons (SGNs) make afferent synapses on the auditory sensory cells, the inner hair cells (IHCs), and convey auditory information to the brain. Noise damages cochlear afferent synapses even at sound levels too low to destroy hair cells. Noise-induced cochlear “synaptopathy” (NICS) is detectable by histological examination and counting of synapses and is also evident, noninvasively, as reduced auditory brainstem response (ABR) wave I amplitude. While synaptopathy does not detectably affect auditory thresholds, it may cause hearing impairments such as poorer speech-in-noise performance or tinnitus. In the course of investigating means to prevent NICS, we observed that female mice are significantly less susceptible than are males to NICS. Remarkably, female susceptibility varies with estrous cycle phase, with lowest susceptibility correlated with the estrous phase at which progesterone (P4) levels are highest (and estrogen lowest). In vitro experiments additionally show that a high level of P4 promotes rapid regeneration of synapses. These data showing sex differences in synaptopathy are the first to show that susceptibility varies through the estrous cycle and to show a protective role for P4. To follow up, our first aim is to determine whether a high level of steroid sex hormone does reduce NICS. To that end, we will experimentally manipulate levels of P4 and estrogen in male and female mice. We have further shown that, not only P4 but also the neurotrophic factor CNTF and agents that activate cyclic AMP (cAMP) signaling promote synaptic regeneration. The latter include compounds, such as rolipram, that can be administered systemically. P4, CNTF, and rolipram represent excellent reagents for investigating the role in vivo of cAMP in synapse regeneration and may also be candidate therapeutics for post-noise synapse regeneration therapy. However, cochlear synapses may lose their capacity for regeneration with time after damage and the timecourse may differ among the different agents promoting regeneration. Our second aim will determine how long after noise these agents, P4, CNTF, or cAMP, may be administered and still promote regeneration. Unlike the case for peptide neurotrophic factors, the molecular and cellular mechanism(s) by which progesterone or cAMP promote synapse regeneration remain obscure. Our third aim asks whether these factors function via genomic actions or via cytoplasmic targets or plasma membrane receptors – a necessary preliminary step for future detailed mechanistic studies of signaling pathways and possible transcriptome changes involved. For cAMP, the question is whether cAMP- dependent protein kinase enters the nucleus or remains a cytoplasmic signal, a question we successfully answered previously with respect to survival signaling. For progesterone, our preliminary studies suggest that a nuclear receptor is not involved so our focus will be on plasma membrane progesterone receptors.