scholarly journals Developing Fast, Red-Light Optogenetic Stimulation of Spiral Ganglion Neurons for Future Optical Cochlear Implants

2021 ◽  
Vol 14 ◽  
Author(s):  
Antoine Tarquin Huet ◽  
Tobias Dombrowski ◽  
Vladan Rankovic ◽  
Anupriya Thirumalai ◽  
Tobias Moser
Keyword(s):  
Cochlear Implants ◽  
Viral Vectors ◽  
Red Light ◽  
Spiral Ganglion ◽  
Clinical Translation ◽  
Spiral Ganglion Neurons ◽  
Optogenetic Stimulation ◽  
Brainstem Response ◽  
Ganglion Neurons ◽  
Stimulation Of

Optogenetic stimulation of type I spiral ganglion neurons (SGNs) promises an alternative to the electrical stimulation by current cochlear implants (CIs) for improved hearing restoration by future optical CIs (oCIs). Most of the efforts in using optogenetic stimulation in the cochlea so far used early postnatal injection of viral vectors carrying blue-light activated channelrhodopsins (ChRs) into the cochlea of mice. However, preparing clinical translation of the oCI requires (i) reliable and safe transduction of mature SGNs of further species and (ii) use of long-wavelength light to avoid phototoxicity. Here, we employed a fast variant of the red-light activated channelrhodopsin Chrimson (f-Chrimson) and different AAV variants to implement optogenetic SGN stimulation in Mongolian gerbils. We compared early postnatal (p8) and adult (>8 weeks) AAV administration, employing different protocols for injection of AAV-PHP.B and AAV2/6 into the adult cochlea. Success of the optogenetic manipulation was analyzed by optically evoked auditory brainstem response (oABR) and immunohistochemistry of mid-modiolar cryosections of the cochlea. In order to most efficiently evaluate the immunohistochemical results a semi-automatic procedure to identify transduced cells in confocal images was developed. Our results indicate that the rate of SGN transduction is significantly lower for AAV administration into the adult cochlea compared to early postnatal injection. SGN transduction upon AAV administration into the adult cochlea was largely independent of the chosen viral vector and injection approach. The higher the rate of SGN transduction, the lower were oABR thresholds and the larger were oABR amplitudes. Our results highlight the need to optimize viral vectors and virus administration for efficient optogenetic manipulation of SGNs in the adult cochlea for successful clinical translation of SGN-targeting gene therapy and of the oCI.

scholarly journals Protection of cochlear synapses from noise-induced excitotoxic trauma by blockade of Ca2+-permeable AMPA receptors

2020 ◽  
Vol 117 (7) ◽  
pp. 3828-3838 ◽  
Author(s):  
Ning Hu ◽  
Mark A. Rutherford ◽  
Steven H. Green
Keyword(s):  
Ampa Receptors ◽  
Spiral Ganglion ◽  
Auditory Brainstem ◽  
Spiral Ganglion Neurons ◽  
Loud Sound ◽  
Selective Blockade ◽  
Hearing Thresholds ◽  
Brainstem Response ◽  
Low Threshold ◽  
Ganglion Neurons

Exposure to loud sound damages the postsynaptic terminals of spiral ganglion neurons (SGNs) on cochlear inner hair cells (IHCs), resulting in loss of synapses, a process termed synaptopathy. Glutamatergic neurotransmission via α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)-type receptors is required for synaptopathy, and here we identify a possible involvement of GluA2-lacking Ca2+-permeable AMPA receptors (CP-AMPARs) using IEM-1460, which has been shown to block GluA2-lacking AMPARs. In CBA/CaJ mice, a 2-h exposure to 100-dB sound pressure level octave band (8 to 16 kHz) noise results in no permanent threshold shift but does cause significant synaptopathy and a reduction in auditory brainstem response (ABR) wave-I amplitude. Chronic intracochlear perfusion of IEM-1460 in artificial perilymph (AP) into adult CBA/CaJ mice prevented the decrease in ABR wave-I amplitude and the synaptopathy relative to intracochlear perfusion of AP alone. Interestingly, IEM-1460 itself did not affect the ABR threshold, presumably because GluA2-containing AMPARs can sustain sufficient synaptic transmission to evoke low-threshold responses during blockade of GluA2-lacking AMPARs. On individual postsynaptic densities, we observed GluA2-lacking nanodomains alongside regions with robust GluA2 expression, consistent with the idea that individual synapses have both CP-AMPARs and Ca2+-impermeable AMPARs. SGNs innervating the same IHC differ in their relative vulnerability to noise. We found local heterogeneity among synapses in the relative abundance of GluA2 subunits that may underlie such differences in vulnerability. We propose a role for GluA2-lacking CP-AMPARs in noise-induced cochlear synaptopathy whereby differences among synapses account for differences in excitotoxic susceptibility. These data suggest a means of maintaining normal hearing thresholds while protecting against noise-induced synaptopathy, via selective blockade of CP-AMPARs.

scholarly journals Syndromic deafness gene ATP6V1B2 controls degeneration of spiral ganglion neurons through modulating proton flux

2021 ◽  
Author(s):  
Shiwei Qiu ◽  
Weihao Zhao ◽  
Xue Gao ◽  
Dapeng Li ◽  
Weiqian Wang ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Hair Cells ◽  
Intraperitoneal Administration ◽  
Spiral Ganglion ◽  
Sensorineural Deafness ◽  
Autophagic Flux ◽  
Spiral Ganglion Neurons ◽  
Distortion Product ◽  
Brainstem Response ◽  
Ganglion Neurons

Abstract ATP6V1B2 encodes the V1B2 subunit in V-ATPase, a proton pump responsible for the acidification of lysosomes. Mutations in this gene cause DDOD syndrome, DOORS syndrome, and Zimmermann-Laband syndrome, which share overlapping feature of congenital sensorineural deafness, onychodystrophy, and different extents of intellectual disability without or with epilepsy. However, the underlying mechanism is unclear. To investigate the pathological role of mutant ATP6V1B2 in the auditory system, we evaluated auditory brainstem response, distortion product otoacoustic emissions, in a transgenic line of mice carrying c.1516 C > T (p.Arg506*) in Atp6v1b2, Atp6v1b2Arg506*/Arg506*. To explore the pathogenic mechanism of neurodegeneration in the auditory pathway, immunostaining, western blotting, and RNAscope analyses were performed in Atp6v1b2Arg506*/Arg506* mice. The Atp6v1b2Arg506*/Arg506* mice showed hidden hearing loss at early stages and developed late-onset hearing loss. We observed increased transcription of Atp6v1b1 in hair cells of Atp6v1b2Arg506*/Arg506* mice and inferred that Atp6v1b1 compensated for the Atp6v1b2 dysfunction by increasing its own transcription level. Genetic compensation in hair cells explains the milder hearing impairment in Atp6v1b2Arg506*/Arg506* mice. Apoptosis activated by lysosomal dysfunction and the subsequent blockade of autophagic flux induced the degeneration of spiral ganglion neurons and further impaired the hearing. Intraperitoneal administration of the apoptosis inhibitor, BIP-V5, improved both phenotypical and pathological outcomes in two live mutant mice. Based on the pathogenesis underlying hearing loss in ATP6V1B2-related syndromes, systemic drug administration to inhibit apoptosis might be an option for restoring the function of spiral ganglion neurons and promoting hearing, which provides a direction for future treatment.

scholarly journals Contralateral Suppression of DPOAEs in Mice after Ouabain Treatment

2018 ◽  
Vol 2018 ◽  
pp. 1-8 ◽  
Author(s):  
Jieying Li ◽  
Yan Chen ◽  
Shan Zeng ◽  
Chuijin Lai ◽  
Yanping Zhang ◽  
...  
Keyword(s):  
Otoacoustic Emissions ◽  
Round Window ◽  
Spiral Ganglion ◽  
Auditory Brainstem ◽  
Spiral Ganglion Neurons ◽  
Type I ◽  
Type Ii ◽  
Contralateral Suppression ◽  
Brainstem Response ◽  
Ganglion Neurons

Medial olivocochlear (MOC) efferent feedback is suggested to protect the ear from acoustic injury and to increase its ability to discriminate sounds against a noisy background. We investigated whether type II spiral ganglion neurons participate in the contralateral suppression of the MOC reflex. The application of ouabain to the round window of the mouse cochlea selectively induced the apoptosis of the type I spiral ganglion neurons, left the peripherin-immunopositive type II spiral ganglion neurons intact, and did not affect outer hairs, as evidenced by the maintenance of the distorted product otoacoustic emissions (DPOAEs). With the ouabain treatment, the threshold of the auditory brainstem response increased significantly and the amplitude of wave I decreased significantly in the ouabain-treated ears, consistent with the loss of type I neurons. Contralateral suppression was measured as reduction in the amplitude of the 2f1−f2 DPOAEs when noise was presented to the opposite ear. Despite the loss of all the type I spiral ganglion neurons, virtually, the amplitude of the contralateral suppression was not significantly different from the control when the suppressor noise was delivered to the treated cochlea. These results are consistent with the type II spiral ganglion neurons providing the sensory input driving contralateral suppression of the MOC reflex.

scholarly journals Survival and stimulation of neurite outgrowth in a serum-free culture of spiral ganglion neurons from adult mice

2007 ◽  
Vol 230 (1-2) ◽  
pp. 17-23 ◽  
Author(s):  
Mauricio Vieira ◽  
Barbara L. Christensen ◽  
Bruce C. Wheeler ◽  
Albert S. Feng ◽  
Richard Kollmar
Keyword(s):  
Neurite Outgrowth ◽  
Spiral Ganglion ◽  
Spiral Ganglion Neurons ◽  
Serum Free ◽  
Adult Mice ◽  
Ganglion Neurons ◽  
Stimulation Of

scholarly journals Sensorineural Hearing Loss and Mitochondrial Apoptosis of Cochlear Spiral Ganglion Neurons in Fibroblast Growth Factor 13 Knockout Mice

2021 ◽  
Vol 15 ◽  
Author(s):  
Yulou Yu ◽  
Jing Yang ◽  
Feng Luan ◽  
Guoqiang Gu ◽  
Ran Zhao ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Inner Ear ◽  
Molecular Mechanisms ◽  
Spiral Ganglion ◽  
Conditional Knockout ◽  
Spiral Ganglion Neurons ◽  
Potential Candidate ◽  
Auditory Function ◽  
Brainstem Response ◽  
Ganglion Neurons

Deafness is known to occur in more than 400 syndromes and accounts for almost 30% of hereditary hearing loss. The molecular mechanisms underlying such syndromic deafness remain unclear. Furthermore, deafness has been a common feature in patients with three main syndromes, the BÖrjeson-Forssman-Lehmann syndrome, Wildervanck syndrome, and Congenital Generalized Hirsutism, all of which are characterized by loss-of-function mutations in the Fgf13 gene. Whether the pathogenesis of deafness in these syndromes is associated with the Fgf13 mutation is not known. To elucidate its role in auditory function, we generated a mouse line with conditional knockout of the Fgf13 gene in the inner ear (Fgf13 cKO). FGF13 is expressed predominantly in the organ of Corti, spiral ganglion neurons (SGNs), stria vascularis, and the supporting cells. Conditional knockout of the gene in the inner ear led to sensorineural deafness with low amplitude and increased latency of wave I in the auditory brainstem response test but had a normal distortion product otoacoustic emission threshold. Fgf13 deficiency resulted in decreased SGN density from the apical to the basal region without significant morphological changes and those in the number of hair cells. TUNEL and caspase-3 immunocytochemistry assays showed that apoptotic cell death mediated the loss of SGNs. Further detection of apoptotic factors through qRT-PCR suggested the activation of the mitochondrial apoptotic pathway in SGNs. Together, this study reveals a novel role for Fgf13 in auditory function, and indicates that the gene could be a potential candidate for understanding deafness. These findings may provide new perspectives on the molecular mechanisms and novel therapeutic targets for treatment deafness.

scholarly journals Cochlear implants and ex vivo BDNF gene therapy protect spiral ganglion neurons

2007 ◽  
Vol 228 (1-2) ◽  
pp. 180-187 ◽  
Author(s):  
Darius Rejali ◽  
Valerie A. Lee ◽  
Karen A. Abrashkin ◽  
Nousheen Humayun ◽  
Donald L. Swiderski ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Cochlear Implants ◽  
Ex Vivo ◽  
Spiral Ganglion ◽  
Spiral Ganglion Neurons ◽  
Bdnf Gene ◽  
Ganglion Neurons
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