Auditory brainstem neural activation patterns are altered in EphA4‐ and ephrin‐B2‐deficient mice

Abstract

Auditory processing requires proper formation of tonotopically ordered projections. We have evaluated the role of an Eph receptor tyrosine kinase and an ephrin ligand in the development of these frequency maps. We demonstrated expression of EphA4 and ephrin-B2 in auditory nuclei and found expression gradients along the frequency axis in neonates. We tested the roles of EphA4 and ephrin-B2 in development of auditory projections by evaluating whether mutations result in altered patterns of expression of the immediate early gene c-fos after exposure to pure tone stimuli. We evaluated two nuclei, the dorsal cochlear nucleus (DCN) and the medial nucleus of the trapezoid body (MNTB), which project in two distinct auditory pathways. The mean number of c-fos-positive neurons in EphA4(-/-) DCN after 8-kHz pure tone stimulation was 42% lower than in wild-type DCN. Along the dorsoventral, tonotopic axis of DCN, the mean position of c-fos-positive neurons was similar for mutant and wild-type mice, but the spread of these neurons along the tonotopic axis was 35% greater for ephrin-B2(lacZ/+) mice than for wild-type mice. We also examined these parameters in MNTB after exposure to 40-kHz pure tones. Both EphA4(-/-) and ephrin-B2(lacZ/+) mice had significantly fewer c-fos-positive cells than wild-type littermates. The labeled band of cells was narrower and laterally shifted in EphA4(-/-) mice compared with wild-type mice. These differences in cell number and distribution suggest that EphA4 and ephrin-B2 signaling influence auditory activation patterns.

Comparative posthearing development of inhibitory inputs to the lateral superior olive in gerbils and mice

“…Already at hearing onset, frequency tuning of the excitatory and the inhibitory inputs is matched (Sanes and Rubel 1988), and thus the general tonotopic alignment of inputs occurs independent of sound experience. Various guidance molecules, most notably the ephrins, seem to play an important role in this process (Huffman and Cramer 2007;Miko et al 2007). Comparing the development of the frequency response areas of the inhibitory and excitatory inputs to LSO neurons, however, suggests a further but small functional tonotopic refinement of the inputs, which occurs after hearing onset (Sanes and Rubel 1988).…”

The emerging framework of mammalian auditory hindbrain development

“…The Eph-ephrin system does not only play a role in rhombomere boundary formation but also in the establishment of auditory hindbrain circuits (Cramer and Gabriele 2014). Ephrin B2 and EphA4 seem to be needed for the formation of appropriately restricted tonotopic maps in the DCN and MNTB, as altered frequency maps were observed in mice without EphA4 or with reduced levels of ephrin B2 (Miko et al 2007). The VCN-MNTB projection is normally strictly contralateral but the number of ipsilateral terminations significantly increases, when either ephrin B2, or EphB2 together with EphB3 are eliminated in mice (Hsieh et al 2010;Nakamura and Cramer 2011).…”

The Cochlear Implant in Action: Molecular Changes Induced in the Rat Central Auditory System

“…Expression of c-Fos has been seen in central auditory neurons after acoustical or electrical stimulation of the ear. Using pure-tone stimulation of mice or rats, the locations of neurons that turn positive for c-Fos or its mRNA were found to match the electrophysiologically established tonotopic maps in the ventral and dorsal cochlear nucleus (Rouiller et al, 1992;Brown & Liu, 1995;Miko et al, 2007), the superior olive (Adams, 1995), the dorsal nucleus of the lateral lemniscus (Saint Marie et al, 1999A), the inferior colliculus (Ehret & Fischer, 1991;Friauf, 1995;Pierson & Snyder-Keller, 1994;Saint Marie et al, 1999B), and the auditory cortex . It was also induced in the vestibular nuclei (Sato et al, 1993).…”

“…The neuronal response reflected by c-Fos expression is related to the selective response of different subpopulations of neurons to sounds of timevarying properties (Lu et al, 2009) and may be induced by disinhibition following nerve lesions (Luo et al, 1999). The precision of a tonotopic c-Fos response to pure tone stimulation appears to be under the control of EphA4 and ephrin-B2 (Miko et al, 2007).…”