AUTHOR=Stephani Friederike , Scheuer Veronika , Eckrich Tobias , Blum Kerstin , Wang Wenying , Obermair Gerald J. , Engel Jutta TITLE=Deletion of the Ca2+ Channel Subunit α2δ3 Differentially Affects Cav2.1 and Cav2.2 Currents in Cultured Spiral Ganglion Neurons Before and After the Onset of Hearing JOURNAL=Frontiers in Cellular Neuroscience VOLUME=13 YEAR=2019 URL=https://www.frontiersin.org/journals/cellular-neuroscience/articles/10.3389/fncel.2019.00278 DOI=10.3389/fncel.2019.00278 ISSN=1662-5102 ABSTRACT=

Voltage-gated Ca²⁺ channels are composed of a pore-forming α₁ subunit and auxiliary β and α₂δ subunits, which modulate Ca²⁺ current properties and channel trafficking. So far, the partial redundancy and specificity of α₁ for α₂δ subunits in the CNS have remained largely elusive. Mature spiral ganglion (SG) neurons express α₂δ subunit isoforms 1, 2, and 3 and multiple Ca²⁺ channel subtypes. Differentiation and in vivo functions of their endbulb of Held synapses, which rely on presynaptic P/Q channels (Lin et al., 2011), require the α₂δ3 subunit (Pirone et al., 2014). This led us to hypothesize that P/Q channels may preferentially co-assemble with α₂δ3. Using a dissociated primary culture, we analyzed the effects of α₂δ3 deletion on somatic Ca²⁺ currents (I_Ca) of SG neurons isolated at postnatal day 20 (P20), when the cochlea is regarded to be mature. P/Q currents were the dominating steady-state Ca²⁺ currents (54% of total) followed by T-type, L-type, N-type, and R-type currents. Deletion of α₂δ3 reduced P/Q- and R-type currents by 60 and 38%, respectively, whereas L-type, N-type, and T-type currents were not altered. A subset of I_Ca types was also analyzed in SG neurons isolated at P5, i.e., before the onset of hearing (P12). Both L-type and N-type current amplitudes of wildtype SG neurons were larger at P5 compared with P20. Deletion of α₂δ3 reduced L-type and N-type currents by 23 and 44%, respectively. In contrast, small P/Q currents, which were just being up-regulated at P5, were unaffected by the lack of α₂δ3. In summary, α₂δ3 regulates amplitudes of L- and N-type currents of immature cultured SG neurons, whereas it regulates P/Q- and R-type currents at P20. Our data indicate a developmental switch from dominating somatic N- to P/Q-type currents in cultured SG neurons. A switch from N- to P/Q-type channels, which has been observed at several central synapses, may also occur at developing endbulbs of Held. In this case, reduction of both neonatal N- (P5) and more mature P/Q-type currents (around/after hearing onset) may contribute to the impaired morphology and function of endbulb synapses in α₂δ3-deficient mice.