Adenomatous polyposis coli protein deletion leads to altered cochlear threshold sensitivity and ribbon synapse size.
hearing requires proper differentiation of afferent ribbon synapses between inner hair
cells (IHCs) and spiral ganglion neurons (SGNs), primary sensory neurons that carry
acoustic information to the brain. Within individual IHCs, presynaptic ribbons show a
size gradient with larger ribbons on the modiolar face and smaller ribbons on the pillar
face. This morphological gradient ... read moreis associated with a gradient of spontaneous rates and
threshold sensitivities, which is essential for the broad dynamic range of hearing.
Despite their importance for hearing, mechanisms that direct ribbon differentiation are
poorly defined. We recently identified adenomatous polyposis coli protein (APC) as a key
regulator of interneuronal synapse maturation. Here, I show that APC is required for
ribbon size heterogeneity and normal hearing. Compared with wild-type littermates, APC
conditional knock-out (cKO) mice exhibit decreased auditory brainstem responses. The IHC
ribbon size gradient is also perturbed. Whereas the normal developing IHCs display
ribbon-size gradients before hearing onset, ribbon sizes are aberrant starting from
neonatal ages in APC cKOs. Using reporter mouse lines, I show that the
CamKII-Cre-mediated deletion of floxed APC does not target APC loss to IHCs or SGNs, but
to efferent olivocochlear (OC) neurons that innervate IHCs transiently in neonates, and
SGN fibers at neonatal and mature ages. My findings identify APC and efferent OC inputs
as regulators of ribbon heterogeneity and hearing sensitivity, and show the ribbon size
gradient necessary for dynamic hearing in adults is present neonatally, before hearing
onset. This APC effect on sensory epithelial cell synapses resembles interneuronal and
nerve-muscle synapses, and thereby defines a global role for APC in nicotinic and
glutamatergic synaptic maturation in diverse cell
Thesis (Ph.D.)--Tufts University, 2014.
Submitted to the Dept. of Neuroscience.
Advisors: Michele Jacob, and Maribel Rios.
Committee: Kathleen Dunlap, Peter Juo, and William Sewell.
Keyword: Neurosciences.read less