Cav1.3 Channels Are Essential for Development and Presynaptic Activity of Cochlear Inner Hair Cells

Abstract

Cochlear inner hair cells (IHCs) release neurotransmitter onto afferent auditory nerve fibers in response to sound stimulation. During early development, afferent synaptic transmission is triggered by spontaneous Ca 2+ spikes of IHCS, which are under efferent cholinergic control. Around the onset of hearing, large-conductance Ca 2+-activated K + channels are acquired, and Ca 2+ spikes as well as the cholinergic innervation are lost. Here, we performed patch-clamp measurements in IHCs of mice lacking the mice lacking the Cav1.3 channel (Ca v1.3-/-) to investigate the role of this prevailing voltage-gated Ca 2+ channel in IHC development and synaptic function. The small Ca 2+ current remaining in IHCs from 3-week-old Ca v1.3-/- mice was mainly mediated by L-type Ca 2+ channels, because it was sensitive to dihydropyridines but resistant to inhibitors of non-L-type Ca 2+ channels such as ω-conotoxins GVIA and MVIIC and SNX-482. Depolarization induced only marginal exocytosis in Cav1.3-/- IHC, which was solely mediated by L-type Ca 2+ channels, whereas robust exocytic responses were elicited by photolysis of caged Ca 2+. Secretion triggered by short depolarizations was reduced proportionally to the Ca 2+ current, suggesting that the coupling of the remaining channels to exocytosis was unchanged. Cav1.3-/- IHCs lacked the Ca 2+ action potentials and displayed a complex developmental failure. Most strikingly, we observed a continued presence of efferent cholinergic synaptic transmission and a lack of functional large-conductance Ca 2+-activated K + channels up to 4 weeks after birth. We conclude that Cav1.3 channels are essential for normal hair cell development and synaptic transmission.