L-type Ca(V)1.2 deletion in the cochlea but not in the brainstem reduces noise vulnerability: implication for Ca(V)1.2-mediated control of cochlear BDNF expression

Voltage-gated L-type Ca(2+) channels (L-VGCCs) like Ca(V)1.2 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 Ca(V)1.3, Ca(V)1.2 is also expressed. Due to lethality of constitutive Ca(V)1.2 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 Ca(V)1.2 during this process, two tissue-specific conditional mouse lines were generated. To distinguish the impact of Ca(V)1.2 on the cochlea from that on feedback loops from higher auditory centers Ca(V)1.2 was deleted, in one mouse line, under the Pax2 promoter (Ca(V)1.2(Pax2)) 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 Ca(V)1.2 (Ca(V)1.2(Egr2)) 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 Ca(V)1.2(Pax2) mice, but not in the Ca(V)1.2(Egr2) mice. After noise exposure, Ca(V)1.2(Pax2) 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 Ca(V)1.2(Pax2) mice, we suggest that a Ca(V)1.2-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 Ca(V)1.2 function in efferent circuits.