Role of L-type Ca2+-channels for development and function of the medial nucleus of the trapezoid body, an ultrafast relay center involved in sound localization
Final Report Abstract
Within this project, we characterized both Cacna1cEgr2 and Cacna1dEgr2 mice (missing Cav1.2 and Cav1.3 in the auditory brainstem, respectively) on the anatomical, molecular, cellular, and physiological level. Both channels are required for survival of auditory neurons. Developmental studies identified postnatal day (P)0-4 as the period, when neuronal survival critically depends on Cav1.2 and Cav1.3. Physiological analyses demonstrated elevated ABR waves II and III in Cacna1dEgr2 mice, whereas only minor differences were observed in Cacna1cEgr2 mice. Action potential (AP) parameters of LSO neurons were mostly unchanged in both mouse lines. Notable exception was the half width of the AP, which was reduced by 36% in Cacna1cEgr2 mice, whereas it was increased by 40% in constitutive Cacna1d-/- mice. Thus, Cav1.2 and Cav1.3 show overlapping as well as distinct functions in the developing auditory brainstem. In general, phenotypes are stronger in mice lacking Cav1.3. These data identified an essential central auditory role of the peripheral deafness gene Cacna1d. With respect to signaling, no difference in expression of phosphorylated CREB was identified. In a side project, the role of Cav1.2 in noise trauma was investigated. However, Cacna1cEgr2 mice demonstrated the same amount of threshold elevation as controls. In toto, most objectives of the application were successfully addressed: Initial characterization of the Cacna1dEgr2 mice, the characterization of the Cacna1cEgr2 mice, and the role of Cav1.2 in acoustic trauma. The essential role of Cav1.3 in the central auditory system motivated us to closer look on central auditory functions of deafness genes. This resulted in two reviews. Part of the project was conducted in collaborations with Dr. Morawski, Dr. Monday, and Dr. Rübsamen of the SPP1608, and with Dr. Knipper from Tübingen.
Publications
- (2012) Retrocochlear function of the peripheral deafness gene Cacna1d. Hum Mol Genet. 21.3896-3909
Satheesh SV, Kunert K, Rüttiger L, Zuccotti A, Schönig K, Friauf E, Knipper M, Bartsch D, Nothwang HG
(See online at https://doi.org/10.1093/hmg/dds217) - (2013) 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. Front Mol Neurosci. 2013;6:20
Zuccotti A, Lee SC, Campanelli D, Singer W, Satheesh SV, Patriarchi T, Geisler HS, Köpschall I, Rohbock K, Nothwang HG, Hu J, Hell JW, Schimmang T, Rüttiger L, Knipper M
(See online at https://doi.org/10.3389/fnmol.2013.00020) - (2014) Central auditory functions of deafness genes. Hear Res. 312C:9-20
Willaredt M, Ebbers L, Nothwang HG
(See online at https://doi.org/10.1016/j.heares.2014.02.004) - (2014) L-Type Calcium Channels in the Auditory System. e-Neuroforum 3/2014
Nothwang HG, Engel J, Knipper M, Friauf E
(See online at https://doi.org/10.1007/s13295-014-0059-3) - (2015) L-type calcium channel Cav1.2 is required for maintenance of auditory brainstem nuclei. J Biol Chem. 290: 23692-710
Ebbers L, Somisetty SV, Janz K, Rüttiger L, Blosa M, Hofmann F, Morawski M, Griesemer D, Knipper M, Friauf E, Nothwang, HG
(See online at https://doi.org/10.1074/jbc.M115.672675) - (2015) The emerging framework of mammalian auditory hindbrain development, Cell Tiss Res., 361:33-48
Nothwang HG, Ebbers L, Schlüter T, Willaredt MA
(See online at https://doi.org/10.1007/s00441-014-2110-7)
