4 research outputs found
Phytosterols reverse antiretroviral-induced hearing loss, with potential implications for cochlear aging
Abstract: ACUho:lePslteearsoelccoonnfitrrmibtuhtaetasllthoenaeduinrgolneavel lmsaermerbeprarneseenintetedgcorirtyre,cstulyp:ports membrane protein clustering
and function, and facilitates proper signal transduction. Extensive evidence has
shown that cholesterol imbalances in the central nervous system occur in aging and in the
development of neurodegenerative diseases. In this work, we characterize cholesterol
homeostasis in the inner ear of young and aged mice as a new unexplored possibility for the
prevention and treatment of hearing loss. Our results show that cholesterol levels in the
inner ear are reduced during aging, an effect that is associated with an increased expression
of the cholesterol 24-hydroxylase (CYP46A1), the main enzyme responsible for cholesterol
turnover in the brain. In addition, we show that pharmacological activation of CYP46A1 with
the antiretroviral drug efavirenz reduces the cholesterol content in outer hair cells (OHCs),
leading to a decrease in prestin immunolabeling and resulting in an increase in the distortion
product otoacoustic emissions (DPOAEs) thresholds. Moreover, dietary supplementation
with phytosterols, plant sterols with structure and function similar to cholesterol, was able to
rescue the effect of efavirenz administration on the auditory function. Altogether, our findings
point towards the importance of cholesterol homeostasis in the inner ear as an innovative
therapeutic strategy in preventing and/or delaying hearing loss
Cell-Specific Inducible Gene Recombination in Postnatal Inner Ear Supporting Cells and Glia
Recent studies indicate that supporting cells play important roles in inner ear development, function, and regeneration after injury, but the molecular mechanisms underlying these processes remain poorly understood. Inducible cell-specific gene recombination in supporting cells could be a powerful tool to study the roles of specific molecules in these cells. Here we tested the feasibility, effectiveness, and cell specificity of inducible Cre-mediated gene recombination in the postnatal inner ear using mice that express an inducible form of Cre (CreERT) under the transcriptional control of the proteolipid protein (PLP) promoter. We assessed the pattern of tamoxifen-induced gene recombination in the inner ear using the ROSA26-LacZ reporter line, in which the β-galactosidase gene is expressed only after Cre-mediated excision of a loxP-flanked stop cassette. Recombination was detected in cochlear inner phalangeal cells, supporting cells surrounding hair cells in vestibular maculae and cristae. Recombination also occurred in Schwann cells. We also found that this CreERT line can be used to increase and decrease the levels of expression of a trophic factor, brain-derived neurotrophic factor, specifically in supporting cells. These results show that PLP/CreERT mice are a powerful tool to dissect gene function in inner ear supporting cells
Electrical Properties and Functional Expression of Ionic Channels in Cochlear Inner Hair Cells of Mice Lacking the α10 Nicotinic Cholinergic Receptor Subunit
Cochlear inner hair cells (IHCs) release neurotransmitter onto afferent auditory nerve fibers in response to sound stimulation. During early development, synaptic transmission is triggered by spontaneous Ca2+ spikes which are modulated by an efferent cholinergic innervation to IHCs. This synapse is inhibitory and mediated by the α9α10 nicotinic cholinergic receptor (nAChR). After the onset of hearing, large-conductance Ca2+-activated K+ channels are acquired and both the spiking activity and the efferent innervation disappear from IHCs. In this work, we studied the developmental changes in the membrane properties of cochlear IHCs from α10 nAChR gene (Chrna10) “knockout” mice. Electrophysiological properties of IHCs were studied by whole-cell recordings in acutely excised apical turns of the organ of Corti from developing mice. Neither the spiking activity nor the developmental functional expression of voltage-gated and/or calcium-sensitive K+ channels is altered in the absence of the α10 nAChR subunit. The present results show that the α10 nAChR subunit is not essential for the correct establishment of the intrinsic electrical properties of IHCs during development