L-type CaV1.2 deletion in the cochlea but not in the brainstem reduces noise vulnerability: implication for CaV1.2-mediated control of cochlear BDNF expression

Abstract

Voltage-gated L-type Ca2+ channels (L-VGCCs) like CaV1.2 are assumed to play a crucial role for controlling release of trophic peptides including brain-derived neurotrophic factor (BDNF). In the inner ear of the adult mouse, besides the well-described L-VGCC CaV1.3, CaV1.2 is also expressed. Due to lethality of constitutive CaV1.2 knock-out mice, the function of this ion channel as well as its putative relationship to BDNF in the auditory system is entirely elusive. We recently described that BDNF plays a differential role for inner hair cell (IHC) vesicles release in normal and traumatized condition. To elucidate a presumptive role of CaV1.2 during this process, two tissue-specific conditional mouse lines were generated. To distinguish the impact of CaV1.2 on the cochlea from that on feedback loops from higher auditory centers CaV1.2 was deleted, in one mouse line, under the Pax2 promoter (CaV1.2Pax2) leading to a deletion in the spiral ganglion neurons, dorsal cochlear nucleus, and inferior colliculus. In the second mouse line, the Egr2 promoter was used for deleting CaV1.2 (CaV1.2Egr2) in auditory brainstem nuclei. In both mouse lines, normal hearing threshold and equal number of IHC release sites were observed. We found a slight reduction of auditory brainstem response wave I amplitudes in the CaV1.2Pax2 mice, but not in the CaV1.2Egr2 mice. After noise exposure, CaV1.2Pax2 mice had less-pronounced hearing loss that correlated with maintenance of ribbons in IHCs and less reduced activity in auditory nerve fibers, as well as in higher brain centers at supra-threshold sound stimulation. As reduced cochlear BDNF mRNA levels were found in CaV1.2Pax2 mice, we suggest that a CaV1.2-dependent step may participate in triggering part of the beneficial and deteriorating effects of cochlear BDNF in intact systems and during noise exposure through a pathway that is independent of CaV1.2 function in efferent circuits.

Noise induced reversible changes of cochlear ribbon synapses contribute to temporary hearing loss in mice

“…Amplitude of ABR wave I may reflect changes of synaptic potentials between inner hair cells and nerve fibers of spiral ganglion cells [13]. In this study, wave I peak amplitude was found to reduce immediately after 2 h of exposure to the 110 dB SPL sound stimulation, (p < 0.05, click, Figure 2A), corresponding to the elevations of hearing threshold.…”

The impact of biological sex on the response to noise and otoprotective therapies against acoustic injury in mice

“…This allowed for hearing thresholds to be determined from both ears simultaneously, with each ear considered a separate data point. The results section shows the data with each ear counting as an individual biological replicate because both ears were exposed to noise and thresholds were obtained from the two ears separately, as previously described [ 33 , 34 ]. In addition, the supplementary data reports the hearing threshold results where the thresholds from both ears of each mouse are averaged and each mouse is counted as an individual biological sample.…”

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

“…The ethological results showed that Fgf13 cKO mice displayed impaired auditory function ( Figures 3A–C ) and gene deletion affected the wave I component but not the wave II-V in the click-evoked ABR test ( Figures 3D–F ). These results suggest that Fgf13 deletion selectively causes damage to SGN but not to the central auditory pathway, since the amplitude and peak latency of wave I reflect the function of the peripheral SGNs, whereas waves II-V indicate a function of the ascending auditory pathway ( Zuccotti et al, 2013 ; Eggermont, 2019 ). This observation was further supported by two results, abundant expression of FGF13 in SGNs of the inner ear ( Figure 1 ) as well as that the cKO mice functioned normally in the DPOAE test ( Figure 3G ), indicating an intact function for outer HCs.…”