Supporting cells regulate synapse formation in the vestibular epithelium.

GÓMEZ-CASATI ME

Puerto Rico

Congreso; Pew annual meeting; 2009

Pew Charitable Trust

Supporting cells (SCs) of the vestibular epithelia are closely connected with hair cells and afferent nerve terminals, making them potential contributors to the development and function of hair cell-afferent synapses, however this remains to be verified. Previous studies have implicated erbB receptor signaling in the survival of cochlear sensory neurons. Sensory neurons express the erbB ligand NRG1 while SCs express erbB receptors. To study the role of vestibular SCs we used a transgenic mouse line in which erbB receptor signaling in these cells was 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 examine this potential role we induced over-expression of BDNF in supporting cells at postnatal ages in DN-erbB4 mice. At P21, DN-erbB4 mice that overexpress BDNF in SCs appeared to have functional vestibular systems. Further examination of these mice using vestibular evoked potential recordings confirmed our finding that over-expression of BDNF in supporting cells was sufficient to rescue vestibular function in DN-erbB4 mice. Not surprisingly, these mice also had normal synaptic density.  Together these results indicate that SCs contribute to the formation/maturation of synapses in the utricular maculae and that this is mediated by NRG1-erbB and BDNF-TrkB signaling.