EphA4 misexpression alters tonotopic projections in the auditory brainstem

Abstract

Auditory pathways contain orderly representations of frequency selectivity, which begin at the cochlea and are transmitted to the brainstem via topographically ordered axonal pathways. The mechanisms that establish these tonotopic maps are not known. Eph receptor tyrosine kinases and their ligands, the ephrins, have a demonstrated role in establishing topographic projections elsewhere in the brain, including the visual pathway. Here, we have examined the function of these proteins in the formation of auditory frequency maps. In birds, the first central auditory nucleus, n. magnocellularis (NM), projects tonotopically to n. laminaris (NL) on both sides of the brain. We previously showed that the Eph receptor EphA4 is expressed in a tonotopic gradient in the chick NL, with higher frequency regions showing greater expression than lower frequency regions. Here we misexpressed EphA4 in the developing auditory brainstem from embryonic day 2 (E2) through E10, when NM axons make synaptic contact with NL. We then evaluated topography along the frequency axis using both anterograde and retrograde labeling in both the ipsilateral and contralateral NM-NL pathways. We found that after misexpression, NM regions project to a significantly broader proportion of NL than in control embryos, and that both the ipsilateral map and the contralateral map show this increased divergence. These results support a role for EphA4 in establishing tonotopic projections in the auditory system, and further suggest a general role for Eph family proteins in establishing topographic maps in the nervous system.

Synaptic Refinement of an Inhibitory Topographic Map in the Auditory Brainstem Requires Functional CaV1.3 Calcium Channels

“…Not much is known about the mechanisms that establish an initially crude topography in the auditory brainstem, but Eph protein signaling appears to be involved (Huffman and Cramer, 2007). Which steps of the development of topography in the auditory brainstem are influenced by cochlea-driven activity is subject to an ongoing discussion (Kandler et al, 2009).…”

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).…”

Strategies to Improve Music Perception in Cochlear Implantees

“…Mechanisms underlying the development of tonotopic maps remained unknown. In previous studies, however, deprivation of auditory input due to cochlear ablation and/or misexpression of essential proteins in the auditory pathway in neonatal birds and mammals have been shown to affect the normal development of tonotopic maps (Harrison et al, 1998;Huffman & Cramer, 2007;Yu et al, 2007;Zhang et al, 2005). This might in turn lead to a diminished capacity of the auditory system to decode the acoustic information in terms of frequency resolution (Harrison et al, 1998;Huffman & Cramer, 2007;Yu et al, 2007), which could underpin our finding of the insignificant effect for pitch-interval size on the differentiation tasks.…”

“…Topographically arranged representations of frequency-tuning maps (i.e.,tonotopy) have been known to exist in the auditory system (Huffman & Cramer, 2007). The orderly maps of tonotopy start at the cochlea and continue through to the auditory cortex.…”