Re-purposing PDE9 inhibitor as a cognitive enhancer for age-related hearing loss

Increasing evidence suggests that age-related hearing loss is the third leading cause of disability in older adults and the most relevant risk factor for cognitive decline. Older people often report difficulties in speech understanding particularly in complex listening environments which is commonly attributed to cochlear synaptopathy (loss of synapses between the hair cells and the auditory nerve fiber). This usually occurs due to accumulated damage by environmental or occupational noise to the cochlea. Nevertheless, age-related hearing loss frequently remains neglected and undiagnosed for years because of the slow progression of the disease, and clinically non-relevant audiometric screening for cochlear synaptopathy. Interestingly, when hearing loss occurs slowly over a long period, the brain may adapt to the reduced sensory input. This adaptation can take the form of auditory neural gain which compensates for a reduced auditory input in age-related cochlear synaptopathy. We previously described that middle-aged but not old animals can respond to this in two different ways: either with low or high capacity to compensate by amplifying their central neural responses. In the present study, we focused on identifying if it was possible to rescue the low compensators’ endophenotype by re-purposing a cyclic guanosine-monophosphate (cGMP) modulating drug – PDE9 inhibitor- as a cognitive enhancer for cochlear synaptopathy. We surprisingly found that the successful central auditory- and memory-dependent adjustment to cochlear synaptopathy is a cGMP- and glucocorticoid-dependent process supported by the dendritic spine remodeling.