Loss of function mutation of the receptor guanylyl cyclase B (GC-B) leads to changes in features of auditory processing

Abstract

The guanylyl cyclase B (GC-B) was recently shown to be important for proper wiring of sensory axons of dorsal root ganglions (DRGs) as well as cranial sensory ganglions (CSGs) as genetic deletion of GC-B and other components of the GC-B signaling pathway resulted in failure of T-like branches in the spinal cord and the hindbrain, respectively (Schmidt et al. 2007; Schmidt et al. 2009; Schmidt and Rathjen 2010; Ter-Avetisyan et al. 2014). First studies shed light on impaired bifurcation of spiral ganglion neurons (SGNs), whose axons form the auditory nerve (AN), showed disturbed tonotopic representation on the level of the cochlear nucleus (CN) and impaired reliance of AN activity but basic hearing function seemed to be normal (Lu et al. 2014). In contrast, the present study found for the first time that a loss of function mutation of the GC-B gene lead to a basal hearing phenotype using standardized methods for investigation of auditory thresholds, namely auditory brainstem responses (ABRs) and distortion products of the otoacoustic emission (DPOAEs). The discovered loss of sensitivity to recognize acoustic stimuli was not caused by impaired sound transmission in the middle ear but changed outer hair cell (OHC) sensitivity following sound stimulation. Analysis of GC-B expression patterns in the cochlea and the brainstem point to intact cochlear hair cells and supports the abundance of fully differentiated and functional inner and outer hair cells (IHCs and OHCs, respectively). Strikingly, morphological and functional analysis of retrocochlear innervation, which drives efferent feedback control of active cochlear amplification and overall cochlear output, points to reduced efferent innervation and changed efferent modulation of hair cell activity. This argument is supported by disclosure of greatly delayed signal transmission along the afferent auditory pathway with misproportion of synchronous activity in the involved auditory nuclei. Reliance and precision of very fast auditory processing was revealed as detection of amplitude-modulated sounds, especially close to detection threshold, and temporal features regarding acoustic startle response (ASR) and prepulse inhibition (PPI) were changed in constitutive GC-B knockout (KO) mice. First experiments with conditional GC-B and cGKI KO mice confirmed the neuronal basis of the observed auditory threshold phenotype of constitutive GC-B KO mice. Concluded, a severe impairment of wiring of AN fibers within the CN during formation of the ascending auditory pathway leads to a profound hearing phenotype, including deficits in temporal resolution of auditory signals.