AUTHOR=Marchetta Philine , Möhrle Dorit , Eckert Philipp , Reimann Katrin , Wolter Steffen , Tolone Arianna , Lang Isabelle , Wolters Markus , Feil Robert , Engel Jutta , Paquet-Durand François , Kuhn Michaela , Knipper Marlies , Rüttiger Lukas 

TITLE=Guanylyl Cyclase A/cGMP Signaling Slows Hidden, Age- and Acoustic Trauma-Induced Hearing Loss

JOURNAL=Frontiers in Aging Neuroscience

VOLUME=Volume 12 - 2020

YEAR=2020

URL=https://www.frontiersin.org/journals/aging-neuroscience/articles/10.3389/fnagi.2020.00083

DOI=10.3389/fnagi.2020.00083

ISSN=1663-4365

ABSTRACT=In the inner ear, cyclic guanosine monophosphate (cGMP) signaling has been described to facilitate otoprotection, which was previously observed through elevated cGMP levels achieved by phosphodiesterase 5 inhibition. However, to date, the upstream hormone receptor pathways eliciting cGMP production are unclear. Here, we show that mice with a genetic deletion of the gene encoding the cGMP generator guanylyl cyclase (GC)-A, the receptor for atrial and B type natriuretic peptides, display a greater vulnerability of hair cells to hidden hearing loss and noise- and age-dependent hearing loss. This vulnerability was associated with GC-A expression in spiral ganglia and outer hair cells (OHCs) but not in inner hair cells (IHCs). GC-A knockout mice exhibited elevated hearing thresholds, most pronounced for the detection of high-frequency tones. Deficits in OHC input-output function in high-frequency regions were already present in young GC-A-deficient mice, with no signs of accelerated progression of age-related hearing loss or higher vulnerability to acoustic trauma. OHCs in these frequency regions from young GC-A knockout mice exhibited diminished levels of KCNQ4 expression, which is the dominant K+ channel in OHCs, and decreased activation of poly (ADP-ribose) polymerase-1, an enzyme involved in DNA repair. Further, GC-A knockout mice had IHC synapse impairments and reduced amplitudes of auditory brainstem responses that progressed with age and with acoustic trauma, in contrast to OHCs, compared to GC-A wild-type littermates. We conclude that GC A/cGMP-dependent signaling pathways have otoprotective functions and GC-A deletion differentially contributes to hair cell damage in a healthy, aged, or injured system. Thus, augmentation of natriuretic peptide/GC-A signaling likely has potential to overcome hidden and noise-induced hearing loss as well as presbycusis.