Efr3a Insufficiency Attenuates the Degeneration of Spiral Ganglion Neurons after Hair Cell Loss

Abstract

Sensorineural hearing loss (SNHL) is caused by an irreversible impairment of cochlear hair cells and subsequent progressive degeneration of spiral ganglion neurons (SGNs). Eighty-five requiring 3 (Efr3) is a plasma membrane protein conserved from yeast to human, and knockout of Efr3a was reported to facilitate the survival of hippocampal newborn neurons in adult mice. Previously, we found Efr3a expression in the auditory neural pathway is upregulated soon after the destruction of hair cells. Here we conducted a time-course analysis of drug-caused damage to hearing ability, hair cells and SGNs in Efr3a knocking down mice (Efr3a−/+, Efr3a KD) and their wild type littermates. Functional examination showed that both groups of mice suffered from serious hearing loss with a higher level of severity in wild type (WT) mice. Morphologic observation following drugs administration showed that both WT and Efr3a KD mice went through progressive loss of hair cells and SGNs, in association with degenerative changes in the perikarya, intracellular organelles, cell body conformation in SGNs, and the changes of SGNs in WT mice were more severe than in Efr3a KD mice. These beneficial effects of Efr3a KD could be ascribed to an increase in the expression of some neurotrophic factors and their receptors in Efr3a KD mice. Our results indicate that Efr3a insufficiency suppresses drug-caused SNHL neurodegeneration in association with an increase in the expression of some neurotrophic factors and their receptors, which may be targeted in the treatment of neurodegeneration.

Restoring autophagic flux attenuates cochlear spiral ganglion neuron degeneration by promoting TFEB nuclear translocation via inhibiting MTOR

“…Morphological observations (Figures 1 and 2) showed that a single injection of kanamycin sulfate (1 g/kg) and an intraperitoneal injection of furosemide (0.4 g/kg), which was injected 30~45 min after the kanamycin injection, successfully induced SGN degeneration in the cochlea of mice via the destruction of cochlear sensory epithelial cells, which was consistent with the results of our previous studies [19,20]. The structure of the organ of Corti was completely collapsed and disintegrated, nearly no sensory epithelial cells remained on the 30th day after kanamycin and furosemide administration, and the basilar membrane was covered by a continuous layer of flattened cubic epithelial cells.…”

“…Unlike gentamicin (another aminoglycoside drug), which damages hair cells and nerve fibers simultaneously [48], kanamycin does not directly damage mature SGN. With electron and light microscopy, in our previous studies, we found that kanamycin and furosemide destroyed the cochlear sensory epithelial cells of adult mice in a very short period and did not directly injure the soma of SGNs [19,20]. In our previous study about the reinnervation of the regenerated hair cells in the cochleae of chickens, the TEM results showed that the morphological structures of synapses beneath the injured hair cells were normal [44].…”

“…Moreover, as SGNs develop and auditory function increases in young mice, the autophagy levels also increase in the mouse cochleae, indicating that autophagy may play a critical role in SGN development [15]. In pathomorphological terms, the degenerative pattern of SGNs and their nerve endings is similar to that of many neurodegenerative diseases [19,20,51,52]. However, to our knowledge, the connection between autophagy and SGN degeneration has not yet been elucidated.…”

“…The mice were randomly divided into 2 groups. The SGN degenerative group (experimental group) was subcutaneously injected with 1 g/kg kanamycin sulfate (Sigma-Aldrich, E004000), and after 30~45 min, 0.4 g/kg furosemide (Tianjin Pharmaceutical Group, H12020527; 10 mg/ml) was injected intraperitoneally [19,20,51]. Mice in the experimental group were subgrouped on the 5th, 15th, and 30th day after drug administration, with 16 mice in each subgroup.…”

“…At each time point, the middle turn of Corti was carefully obtained from the decalcified cochleae and was prepared for immunofluorescence staining as we previously described [19]. After the tissue was blocked in 0.1 M PBS containing 10% donkey serum (Jackson, 017-000-121) with 0.3% Triton X-100 (Sigma, 9002-93-1) at room temperature for 1 h, it was incubated with a rabbit anti-MYO7A antibody (1: 300; Proteus Bioscience, 25-6790) at 4°C overnight.…”