Repertoire of high voltage-activated Ca2+ channels in the lateral superior olive: functional analysis in wild-type, Cav1.3−/−, and Cav1.2DHP−/− mice

Abstract

Voltage-gated Ca2+ (Cav)1.3 α-subunits of high voltage-activated Ca2+ channels (HVACCs) are essential for Ca2+ influx and transmitter release in cochlear inner hair cells and therefore for signal transmission into the central auditory pathway. Their absence leads to deafness and to striking structural changes in the auditory brain stem, particularly in the lateral superior olive (LSO). Here, we analyzed the contribution of various types of HVACCs to the total Ca2+ current ( ICa) in developing mouse LSO neurons to address several questions: do LSO neurons express functional Cav1.3 channels? What other types of HVACCs are expressed? Are there developmental changes? Do LSO neurons of Cav1.3−/− mice show any compensatory responses, namely, upregulation of other HVACCs? Our electrophysiological and pharmacological results showed the presence of functional Cav1.3 and Cav1.2 channels at both postnatal days 4 and 12. Aside from these L-type channels, LSO neurons also expressed functional P/Q-type, N-type, and, most likely, R-type channels. The relative contribution of the four different subtypes to ICa appeared to be 45%, 29%, 22%, and 4% at postnatal day 12, respectively. The physiological results were flanked and extended by quantitative RT-PCR data. Altogether, LSO neurons displayed a broad repertoire of HVACC subtypes. Genetic ablation of Cav1.3 resulted in functional reorganization of some other HVACCs but did not restore normal ICa properties. Together, our results suggest that several types of HVACCs are of functional relevance for the developing LSO. Whether on-site loss of Cav1.3, i.e., in LSO neurons, contributes to the recently described malformation of the LSO needs to be determined by using tissue-specific Cav1.3−/− animals.