Dataset Information

Structure and Function of Cochlear Gap Junctions and Implications for the Translation of Cochlear Gene Therapies.

ABSTRACT: Connexins (Cxs) are ubiquitous membrane proteins that are found throughout vertebrate organs, acting as building blocks of the gap junctions (GJs) known to play vital roles in the normal function of many organs. Mutations in Cx genes (particularly GJB2, which encodes Cx26) cause approximately half of all cases of congenital hearing loss in newborns. Great progress has been made in understanding GJ function and the molecular mechanisms for the role of Cxs in the cochlea. Data reveal that multiple types of Cxs work together to ensure normal development and function of the cochlea. These findings include many aspects not proposed in the classic K+ recycling theory, such as the formation of normal cochlear morphology (e.g., the opening of the tunnel of Corti), the fine-tuning of the innervation of nerve fibers to the hair cells (HCs), the maturation of the ribbon synapses, and the initiation of the endocochlear potential (EP). New data, especially those collected from targeted modification of major Cx genes in the mouse cochlea, have demonstrated that Cx26 plays an essential role in the postnatal maturation of the cochlea. Studies also show that Cx26 and Cx30 assume very different roles in the EP generation, given that only Cx26 is required for normal hearing. This article will review our current understanding of the molecular structure, cellular distribution, and major functions of cochlear GJs. Potential implications of the knowledge of cochlear GJs on the design and implementation of translational studies of cochlear gene therapies for Cx mutations are also discussed.

SUBMITTER: Wu X

PROVIDER: S-EPMC6892400 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Structure and Function of Cochlear Gap Junctions and Implications for the Translation of Cochlear Gene Therapies.

Wu Xuewen X Zhang Wenjuan W Li Yihui Y Lin Xi X

Frontiers in cellular neuroscience 20191127

Connexins (Cxs) are ubiquitous membrane proteins that are found throughout vertebrate organs, acting as building blocks of the gap junctions (GJs) known to play vital roles in the normal function of many organs. Mutations in Cx genes (particularly <i>GJB2</i>, which encodes Cx26) cause approximately half of all cases of congenital hearing loss in newborns. Great progress has been made in understanding GJ function and the molecular mechanisms for the role of Cxs in the cochlea. Data reveal that m ...[more]

PMID: 31827424

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Project description:It is critical for hearing that the descending cochlear efferent system provides a negative feedback to hair cells to regulate hearing sensitivity and protect hearing from noise. The medial olivocochlear (MOC) efferent nerves project to outer hair cells (OHCs) to regulate OHC electromotility, which is an active cochlear amplifier and can increase hearing sensitivity. Here, we report that the MOC efferent nerves also could innervate supporting cells (SCs) in the vicinity of OHCs to regulate hearing sensitivity. MOC nerve fibers are cholinergic, and acetylcholine (ACh) is a primary neurotransmitter. Immunofluorescent staining showed that MOC nerve endings, presynaptic vesicular acetylcholine transporters (VAChTs), and postsynaptic ACh receptors were visible at SCs and in the SC area. Application of ACh in SCs could evoke a typical inward current and reduce gap junctions (GJs) between them, which consequently enhanced the direct effect of ACh on OHCs to shift but not eliminate OHC electromotility. This indirect, GJ-mediated inhibition had a long-lasting influence. In vivo experiments further demonstrated that deficiency of this GJ-mediated efferent pathway decreased the regulation of active cochlear amplification and compromised the protection against noise. In particular, distortion product otoacoustic emission (DPOAE) showed a delayed reduction after noise exposure. Our findings reveal a new pathway for the MOC efferent system via innervating SCs to control active cochlear amplification and hearing sensitivity. These data also suggest that this SC GJ-mediated efferent pathway may play a critical role in long-term efferent inhibition and is required for protection of hearing from noise trauma.NEW & NOTEWORTHY The cochlear efferent system provides a negative feedback to control hair cell activity and hearing sensitivity and plays a critical role in noise protection. We reveal a new efferent control pathway in which medial olivocochlear efferent fibers have innervations with cochlear supporting cells to control their gap junctions, therefore regulating outer hair cell electromotility and hearing sensitivity. This supporting cell gap junction-mediated efferent control pathway is required for the protection of hearing from noise.

Project description:PurposeTo characterize retinal structure and function in achromatopsia (ACHM) in preparation for clinical trials of gene therapy.DesignCross-sectional study.ParticipantsForty subjects with ACHM.MethodsAll subjects underwent spectral domain optical coherence tomography (SD-OCT), microperimetry, and molecular genetic testing. Foveal structure on SD-OCT was graded into 5 distinct categories: (1) continuous inner segment ellipsoid (ISe), (2) ISe disruption, (3) ISe absence, (4) presence of a hyporeflective zone (HRZ), and (5) outer retinal atrophy including retinal pigment epithelial loss. Foveal and outer nuclear layer (ONL) thickness was measured and presence of hypoplasia determined.Main outcome measuresPhotoreceptor appearance on SD-OCT imaging, foveal and ONL thickness, presence of foveal hypoplasia, retinal sensitivity and fixation stability, and association of these parameters with age and genotype.ResultsForty subjects with a mean age of 24.9 years (range, 6-52 years) were included. Disease-causing variants were found in CNGA3 (n = 18), CNGB3 (n = 15), GNAT2 (n = 4), and PDE6C (n = 1). No variants were found in 2 individuals. In all, 22.5% of subjects had a continuous ISe layer at the fovea, 27.5% had ISe disruption, 20% had an absent ISe layer, 22.5% had an HRZ, and 7.5% had outer retinal atrophy. No significant differences in age (P = 0.77), mean retinal sensitivity (P = 0.21), or fixation stability (P = 0.34) across the 5 SD-OCT categories were evident. No correlation was found between age and foveal thickness (P = 0.84) or between age and foveal ONL thickness (P = 0.12).ConclusionsThe lack of a clear association of disruption of retinal structure or function in ACHM with age suggests that the window of opportunity for intervention by gene therapy is wider in some individuals than previously indicated. Therefore, the potential benefit for a given subject is likely to be better predicted by specific measurement of photoreceptor structure rather than simply by age. The ability to directly assess cone photoreceptor preservation with SD-OCT and/or adaptive optics imaging is likely to prove invaluable in selecting subjects for future trials and measuring the trials' impact.

Dataset Information

Structure and Function of Cochlear Gap Junctions and Implications for the Translation of Cochlear Gene Therapies.

Publications

Structure and Function of Cochlear Gap Junctions and Implications for the Translation of Cochlear Gene Therapies.

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