cGMP Signaling as a Molecular Target for Central Adaptation in Age-Related Cochlear Synaptopathy

Abstract

Age-related hearing loss may gradually occur over the years due to adverse effects of accumulated environmental or occupational noise exposure. Cochlear synaptopathy is a condition where the synapses between the hair cells in the cochlea and the auditory nerve fibers are damaged. This damage can lead to difficulties in hearing, especially in noisy environments. This condition can contribute to age-related hearing loss and has been linked with impaired auditory perception and temporal auditory processing, which is crucial for understanding speech, particularly in complex listening environments. However, cochlear synaptopathy does not necessarily lead to temporal resolution deficits when the reduced auditory input is compensated by midbrain responses (neural gain). Individuals may vary in their ability to compensate for cochlear synaptopathy with low compensators showing reduced central compensation abilities and high compensators exhibiting robust compensation. In our studies, we aimed to identify the underlying mechanisms for central auditory compensation. Given that central auditory compensation needs a memory-dependent adaptation process, we investigated a cognitive enhancer, a PDE9A inhibitor. PDE9A inhibitor is suggested to have positive effects on learning and memory by increasing cGMP levels. To test this, we used an animal model involving middle-aged mice. During these studies, we observed that high compensators had elevated corticosterone levels in response to stress (vehicle injections) while low compensators did not show this response. In high compensators, stress led to several negative effects on auditory processing, inner hair cell function, LTP, and BDNF expression which were not observed in low compensators. Treatment with PDE9A inhibitor reversed the negative effects of stress in high compensators but did not show improvements in low compensators. On the other hand, temporal coding in low compensators was less precise than in high compensators which were not improved by the treatment with PDE9A inhibitor. Further analysis of LTD measurement and the dendritic spine remodeling confirmed that low compensators have reduced capacity for developing adaptation high compensators, but not low compensators, exhibited LTD adjustment and higher amount of learning spines which were also impaired through vehicle injection and prevented by PDE9A inhibitor treatment. We could show that the ability to centrally compensate for cochlear synaptopathy is a mechanism dependent on glucocorticoid and cGMP. Hence, we suggest that a blunted stress response can lead to a failure in this compensation mechanism, potentially contributing to the link between hearing loss and dementia. Further, we investigated the role of stress receptors MR and GR in the modulation of the stress response, particularly in auditory processing and hippocampal synaptic plasticity. We could reveal that MR cKO mice were able to compensate for reduced auditory nerve activity in the higher auditory pathway, while GR cKO mice were not. Additionally, we checked for the expression of cGMP generators and Arc for the synaptic plasticity regulator. Changes in LTP in both MR cKO and GR cKO mice were more closely related to their central compensation capacity, indicating a postsynaptic mechanism. The deletion of MR influences the expression of GR, NO-GC, and Arc, all of which are involved in the regulation of auditory pathway compensation. The GC-A expression and ABR Wave IV/I ratio, as a measure for compensation, were enhanced in MR cKO mice, that have elevated GR, but were lower or unchanged in GR cKO mice with impaired GR expression. This suggests that GR-dependent processes might influence LTP and auditory neural gain through GC-A. Finally, for the hippocampal synaptic plasticity, we investigated the role of large conductance Ca2+ - and voltage activated K+ channels (BK channels) in cognitive functions. Particularly in learning and memory by specifically deleting BK in CA1 pyramidal neurons. Our results revealed impaired electrical and chemical LTP in cKO brain slices compared to controls in addition to impaired memory acquisition and retrieval in the Morris Water Maze and altered dynamics of intracellular K+ and Ca2+ concentration during synaptic plasticity events in LTP. These findings suggest that BK channels play an important role in hippocampal LTP by mediating potassium outflow which is crucial for the induction of LTP and significantly contributes to learning and memory.