Abstract
The spiral ganglion neurons constitute the primary connection between auditory hair cells and the brain. The spiral ganglion afferent fibers and their synapse with hair cells do not regenerate to any significant degree in adult mammalian ears after damage. We have investigated gene expression changes after kainate-induced disruption of the synapses in a neonatal cochlear explant model in which peripheral fibers and the afferent synapse do regenerate. We compared gene expression early after damage, during regeneration of the fibers and synapses, and after completion of in vitro regeneration. These analyses revealed a total of 2.5% differentially regulated transcripts (588 out of 24,000) based on a threshold of p<0.005. Inflammatory response genes as well as genes involved in regeneration of neural circuits were upregulated in the spiral ganglion neurons and organ of Corti, where the hair cells reside. Prominent genes upregulated at several time points included genes with roles in neurogenesis (Elavl4 and Sox21), neural outgrowth (Ntrk3 and Ppp1r1c), axonal guidance (Rgmb and Sema7a), synaptogenesis (Nlgn2 and Psd2), and synaptic vesicular function (Syt8 and Syn1). Immunohistochemical and in situ hybridization analysis of genes that had not previously been described in the cochlea confirmed their cochlear expression. The time course of expression of these genes suggests that kainate treatment resulted in a two-phase response in spiral ganglion neurons: an acute response consistent with inflammation, followed by an upregulation of neural regeneration genes. Identification of the genes activated during regeneration of these fibers suggests candidates that could be targeted to enhance regeneration in adult ears.
Highlights
Regeneration of auditory neurons and their peripheral fibers would be clinically significant because auditory nerve and hair cell synaptic dysfunction often accompanies hearing loss
We have shown that inhibition of guidance molecules such as repulsive guidance molecule a (RGMa) [7] and neurotrophins [6] promotes new synapses with hair cells, whereas a lack of glutamate at the synapse decreases afferent synaptogenesis [6]
Synaptic regeneration after kainate treatment of cochlear explants The terminal processes of spiral ganglion neurons on hair cells are lost after kainate exposure due to excitotoxic lesioning of the synapses in the cochlea, but regenerate over the 72 h [9]
Summary
Regeneration of auditory neurons and their peripheral fibers would be clinically significant because auditory nerve and hair cell synaptic dysfunction often accompanies hearing loss. Peripheral fiber retraction has been suggested to be reversible in rats after similar damage [5], but quantitative studies of the fate of spiral ganglion neurons after noise-induced loss of terminals showed no evidence for synaptic recovery in mature animals [1]. This is the only peripheral nerve that has no ability to regenerate
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