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.
Highlights
Activity-dependent gene transcription is functionally relevant for animals to acquire information and adapt to the environment
CaV1.2 is assumed to participate in altering synapse efficacy through transcriptional control of brain-derived neurotrophic factor (BDNF; Tabuchi et al, 2000; Zuccotti et al, 2011)
We recently showed that lack of BDNF hampers inner hair cell (IHC) synapse physiology and hearing function while it protects against noise-induced hearing loss (NIHL; Zuccotti et al, 2012)
Summary
Activity-dependent gene transcription is functionally relevant for animals to acquire information and adapt to the environment. Ca2+ influx through voltagegated Ca2+ channels (VGCCs) serves as a key transducer coupling changes in cell surface membrane potential with local intracellular Ca2+ pathways. The BDNF transcription is highly responsive to neural activity. It is up-regulated by learning (Hall et al, 2000; Lubin et al, 2008), physical exercise (Neeper et al, 1995), and kindling or kainate-induced seizures (Dugich-Djordjevic et al, 1992). The L-VGCCs contribute to the asynchronous release of neurotrophins like BDNF from individual vesicles (Barg et al, 2002; Kolarow et al, 2007), which is most probably CaV1.2 dependent (Kolarow et al, 2007). The BDNF transcribed from exon IV is expressed in the inner ear (Schimmang et al, 2003) and is changed after ototoxic drug treatment through Ca2+-responsive
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