GC-B Deficient Mice With Axon Bifurcation Loss Exhibit Compromised Auditory Processing

Abstract

Sensory axon T-like branching (bifurcation) in neurons from dorsal root ganglia and cranial sensory ganglia depends on the molecular signaling cascade involving the secreted factor C-type natriuretic peptide, the natriuretic peptide receptor guanylyl cyclase B (GC-B; also known as Npr2) and cGMP-dependent protein kinase I (cGKI, also known as PKGI). The bifurcation of cranial nerves is suggested to be important for information processing by second-order neurons in the hindbrain or spinal cord. Indeed, mice with a spontaneous GC-B loss of function mutation (Npr2cn/cn) display an impaired bifurcation of auditory nerve (AN) fibers. However, these mice did not show any obvious sign of impaired basal hearing. Here, we demonstrate that mice with a targeted inactivation of the GC-B gene (Npr2lacZ/lacZ, GC-B KO mice) show an elevation of audiometric thresholds. In the inner ear, the cochlear hair cells in GC-B KO mice were nevertheless similar to those from wild type mice, justified by the typical expression of functionally relevant marker proteins. However, efferent cholinergic feedback to inner and outer hair cells was reduced in GC-B KO mice, linked to very likely reduced rapid efferent feedback. Sound-evoked AN responses of GC-B KO mice were elevated, a feature that is known to occur when the efferent axo-dendritic feedback on AN is compromised. Furthermore, late sound-evoked brainstem responses were significantly delayed in GC-B KO mice. This delay in sound response was accompanied by a weaker sensitivity of the auditory steady state response to amplitude-modulated sound stimuli. Finally, the acoustic startle response (ASR) – one of the fastest auditory responses – and the prepulse inhibition of the ASR indicated significant changes in temporal precision of auditory processing. These findings suggest that GC-B-controlled axon bifurcation of spiral ganglion neurons is important for proper activation of second-order neurons in the hindbrain and is a prerequisite for proper temporal auditory processing likely by establishing accurate efferent top-down control circuits. These data hypothesize that the bifurcation pattern of cranial nerves is important to shape spatial and temporal information processing for sensory feedback control.

Atrial Natriuretic Peptide Improves Neurite Outgrowth from Spiral Ganglion Neurons In Vitro through a cGMP-Dependent Manner

“…Interestingly, the same phenomenon was also found in the cranial sensory ganglion neurons entering the hindbrain including cochlear SGNs [84][85][86][87][88]. Likewise, the mouse lacking cGMP-dependent protein kinase 1 (PKG1) or NPR-B has a defect in the central axonal projection of the DRG sensory neurons [74][75][76][77][78][81][82][83] or SGNs [84][85][86][87][88], respectively. Consequently, all these results emphasize a strong significance of the CNP/NPR-B/cGMP/PKG1 pathway regulating neurite outgrowth or pathfinding during neuronal development.…”

“…cGMP signaling elicited by activation of the transmembrane GC-coupled natriuretic peptide receptor NPR-B (also known as NPR2 or GC-B) by the ligand CNP control sensory axon bifurcation of DRG neurons entering the spinal cord [74][75][76][77][78][79][80][81][82][83]. Interestingly, the same phenomenon was also found in the cranial sensory ganglion neurons entering the hindbrain including cochlear SGNs [84][85][86][87][88]. Likewise, the mouse lacking cGMP-dependent protein kinase 1 (PKG1) or NPR-B has a defect in the central axonal projection of the DRG sensory neurons [74][75][76][77][78][81][82][83] or SGNs [84][85][86][87][88], respectively.…”

Deletion of BDNF in Pax2 Lineage-Derived Interneuron Precursors in the Hindbrain Hampers the Proportion of Excitation/Inhibition, Learning, and Behavior

“…The hearing function of adult Bdnf Pax 2 KO and controls was studied by measuring and analyzing auditory brainstem responses ( ABR ) and auditory steady-state responses ( ASSR ), as previously described ( Zuccotti et al, 2012 ; Rüttiger et al, 2013 ; Wolter et al, 2018 ). Animals were exposed to enriching sound as described ( Matt et al, 2018 ).…”

Sensory Neurons: The Formation of T-Shaped Branches Is Dependent on a cGMP-Dependent Signaling Cascade

“…The absence of Npr2 activity in either a spontaneous Npr2 loss of function mutant or due to targeted gene inactivation caused a lack of bifurcation in central axons of spiral ganglion neurons at the brainstem (Lu and others 2011; Ter-Avetisyan and others 2014) and also a transiently overshooting extension of auditory nerve projections beyond rhombomere 2 into the cerebellum (Schmidt and Fritzsch 2019). Functional tests revealed a decreased activation and temporal processing of second-order neurons in the hindbrain, suggesting that axon bifurcation of spiral ganglion neurons might be important for shaping spatial and temporal information processing of sensory feedback (Lu and others 2014; Wolter and others 2018).…”