Mutation of Npr2 Leads to Blurred Tonotopic Organization of Central Auditory Circuits in Mice

Abstract

Tonotopy is a fundamental organizational feature of the auditory system. Sounds are encoded by the spatial and temporal patterns of electrical activity in spiral ganglion neurons (SGNs) and are transmitted via tonotopically ordered processes from the cochlea through the eighth nerve to the cochlear nuclei. Upon reaching the brainstem, SGN axons bifurcate in a stereotyped pattern, innervating target neurons in the anteroventral cochlear nucleus (aVCN) with one branch and in the posteroventral and dorsal cochlear nuclei (pVCN and DCN) with the other. Each branch is tonotopically organized, thereby distributing acoustic information systematically along multiple parallel pathways for processing in the brainstem. In mice with a mutation in the receptor guanylyl cyclase Npr2, this spatial organization is disrupted. Peripheral SGN processes appear normal, but central SGN processes fail to bifurcate and are disorganized as they exit the auditory nerve. Within the cochlear nuclei, the tonotopic organization of the SGN terminal arbors is blurred and the aVCN is underinnervated with a reduced convergence of SGN inputs onto target neurons. The tonotopy of circuitry within the cochlear nuclei is also degraded, as revealed by changes in the topographic mapping of tuberculoventral cell projections from DCN to VCN. Nonetheless, Npr2 mutant SGN axons are able to transmit acoustic information with normal sensitivity and timing, as revealed by auditory brainstem responses and electrophysiological recordings from VCN neurons. Although most features of signal transmission are normal, intermittent failures were observed in responses to trains of shocks, likely due to a failure in action potential conduction at branch points in Npr2 mutant afferent fibers. Our results show that Npr2 is necessary for the precise spatial organization typical of central auditory circuits, but that signals are still transmitted with normal timing, and that mutant mice can hear even with these deficits.

Prickle1 regulates neurite outgrowth of apical spiral ganglion neurons but not hair cell polarity in the murine cochlea

“…It is possible that in the absence of Prickle1, apical SGNs adopt a partial vestibular ganglion neuron phenotype (Fig 4B’, 4D and 4E). Nevertheless, this phenotype is clearly different from the only other afferent disorientation cochlear afferent phenotype reported thus far, Npr2 mutants [64]. Given that branching is clearly more profound in the dorsal cochlear nucleus, it is tempting to speculate that these collaterals are mainly coming from type II afferents known to reach the granular cap [51].…”

Recent advances in the development and function of type II spiral ganglion neurons in the mammalian inner ear

“…Each IHC is innervated by a total of 6-20 type I SGNs in the mature mouse cochlea [26]. Each type I SGN also extends a long central projection that shows a remarkable stereotyped branching pattern, which is dependent on the receptor guanylyl cyclase Npr2 [27]. One branch extends into the anteroventral cochlear nucleus and the second branch crosses the posteroventral cochlear nucleus to terminate at the dorsal cochlear nucleus [8].…”

Optimising 3D scaffold for otic neural progenitor differentiation

“…MMP13, also known as collagenase-3, is a zinc-dependent proteolytic enzyme involved in the remodeling of ECM and is enriched at late developmental stage of SGN (Lu et al, 2011; NCBI, 2016a). NPR2 encodes an integral membrane receptor for natriuretic peptides, which is required for axon bifurcation in SGN and auditory circuit assembly 25,27,28 . NPR2 is highly expressed at very early stage, then dropped in the middle and finally raised again in the late developmental stage of SGN.…”