Supporting Cells Regulate Synapse Formation in the Inner Ear

GÓMEZ-CASATI, ME; MURTIE J; RIO C; STANKOVIC, K; LIBERMAN MC; CORFAS G

Boston, MA, USA

Conferencia; 7th Conference on the Molecular Biology of Hearing and Deafness; 2009

Despite that all vestibular hair cells and their associated sensory nerve terminals are surrounded by supporting cells (SCs), the roles of the SCs in the postnatal vestibular epithelia remained poorly understood. Recent evidence indicates that SCs have many characteristics of glia, including expression of erbB receptors. Furthermore, vestibular sensory neurons express NRG1, an erbB receptor ligand. Since we have and others found that NRG1-erbB signaling is a key regulator of neuron-glia interactions, we tested if erbB signaling in SCs of the vestibular sensory epithelium is important for cell-cell interactions in the vestibular epithelium using a transgenic mouse line in which erbB receptor signaling in these cells is blocked by expression of a dominant-negative erbB receptor (DN-erbB4). At P21, DN-erbB4 mice displayed behaviors consistent with vestibular dysfunction including ataxia, spinning behavior, and inability to swim. Evoked potential recordings showed that vestibular function was severely affected, even though macular epithelia were normal in size and general structure. FM1-43 dye uptake and NFH staining were also normal in mutant mice, indicating that hair cell mechano-transduction and afferent innervation were normal. However, synaptic site numbers (defined as the colocalization of RIBEYE and GluR23 staining) were dramatically reduced, suggesting a synaptic defect. Interestingly, the synaptic alterations were accompanied by a dramatic reduction in BDNF expression in SCs. This is quite remarkable because it has previously been shown that BDNF is essential for normal inner ear development, but there was no evidence that it is also required for synaptogenesis. To clarify its role in the post-natal ear, we developed transgenic lines with inducible BDNF knockout or overexpression specifically in SCs. BDNF knockdown in SCs resulted in vestibular dysfunction and reduced synapse density in the utricle similar to that found in DN-erbB4 mice. Correspondingly, forced expression of BDNF by SCs of DN-erbB4 mice rescued the phenotype, including behavioral, physiological, and morphological measurements. Together, these results indicate that supporting cells contribute to the formation/maturation of synapses in vestibular epithelia and that this contribution is mediated by reciprocal signals between sensory neurons and SCs involving NRG1-erbB and BDNF-TrkB signaling.