cGMP Pathways as Novel Molecular Targets in the Brain for Fast Auditory Processing and Cognitive Function

Abstract

Cyclic guanosine monophosphate (cGMP) signaling as the second messenger of the cGMP/cGKI cascade plays an important role in the auditory system. Particularly GC-A is suggested to be responsible for cGMP-triggered protection or recovery of cochlear components following traumatic overexposure (for review see: Marchetta, Rüttiger et al. 2021). Aiming to get insights into a potential protective role of the cGMP-producing GC-A for auditory processing, global GC-A KO mice were analyzed and shown to display impaired outer hair cell function in young animals already. They also developed a greater vulnerability of inner hair cells to noise- and age-dependent hearing loss, including temporal auditory processing deficits (Marchetta, Möhrle, et al., 2020), suggesting that the stimulation of GC-A signaling may have the potential to prevent or protect from age-dependent auditory fiber loss (cochlear synaptopathy). In the present study a cochlear synaptopathy involving a distinct auditory nerve fiber type (high-SR ANF), was shown to be critical for central compensation and temporal auditory processing. When this fast high SR ANF signaling was attenuated, the driving force to maintain inhibitory strength and to recruit BDNF in capillaries and nerve terminals of the hippocampus during auditory processing and compensation was reduced, which possibly reflected reduced vascular metabolic supply (Eckert, Marchetta et al., 2021; Marchetta et al., in preparation; Marchetta, Savitska et al., 2020). Using tamoxifen-inducible CaMKIIα-Cre mice to delete the stress receptors (mineralo- and glucocorticoid receptors) in the brain, we learned that an interplay of both receptors´ activity might link central hippocampal plasticity changes with peripheral fast auditory processing (Marchetta, Eckert et al., 2022). In conclusion, we could show the importance of development and maintenance of fast auditory processing and would like to introduce cGMP-generators, particularly GC-A, as potential new drug targets to improve auditory processing, stimulate auditory attention and learning-dependent amplification processes.