Presynaptic maturation in auditory hair cells requires a critical period of sensory-independent spiking activity

Abstract

The development of neural circuits relies on spontaneous electrical activity that occurs during immature stages of development. In the developing mammalian auditory system, spontaneous calcium action potentials are generated by inner hair cells (IHCs), which form the primary sensory synapse. It remains unknown whether this electrical activity is required for the functional maturation of the auditory system. We found that sensory-independent electrical activity controls synaptic maturation in IHCs. We used a mouse model in which the potassium channel SK2 is normally overexpressed, but can be modulated in vivo using doxycycline. SK2 overexpression affected the frequency and duration of spontaneous action potentials, which prevented the development of the Ca 2+ -sensitivity of vesicle fusion at IHC ribbon synapses, without affecting their morphology or general cell development. By manipulating the in vivo expression of SK2 channels, we identified the "critical period" during which spiking activity influences IHC synaptic maturation. Here we provide direct evidence that IHC development depends upon a specific temporal pattern of calcium spikes before sound-driven neuronal activity.exocytosis | cochlea | calcium current | kcnn2

α2δ3 Is Essential for Normal Structure and Function of Auditory Nerve Synapses and Is a Novel Candidate for Auditory Processing Disorders

“…Either immature IHCs express very little ␣ 2 ␦3, which we could not consistently amplify with nested RT-PCR, or altered activity in SG or central auditory neurons indirectly affects I Ba and V h . Superior olivary complex neurons exert a transient inhibitory feedback on developing IHCs (Simmons, 2002) that interrupts their spiking activity (Glowatzki and Fuchs, 2000), and impaired feedback can alter IHC gene expression and maturation (Johnson et al, 2013). We conclude that ␣ 2 ␦3 is not the main ␣ 2 ␦ subunit of Ca v 1.3 channel complexes in IHCs, but may play a small role in their development.…”

“…In our study, we currently cannot distinguish between a direct and an indirect role of ␣ 2 ␦3 (via regulating Ca v 2.1 channel expression) for proper ANF synapse formation. Morphological abnormalities of synapses were also found in Purkinje cells (Brodbeck et al, 2002) and at neuromuscular junctions of ␣ 2 ␦2 mutant mice (Kaja et al, 2007). Recently, ␣ 2 ␦1 was identified as the neural thrombospondin receptor responsible for synaptogenesis of central excitatory synapses, further pointing to a role of ␣ 2 ␦ subunits in synaptic structuring (Eroglu et al, 2009).…”

Synaptic transmission between end bulbs of Held and bushy cells in the cochlear nucleus of mice with a mutation in Otoferlin

“…The similarities and differences between two groups of induced deafness and natural deafness mutations provide insights into how spontaneous activity in hair cells before the onset of hearing affects the cochlear nuclei (Johnson et al 2011(Johnson et al , 2013Kros et al 1998;Tritsch et al 2007Tritsch et al , 2010Tritsch and Bergles 2010). Mutations that prevent synaptic transmission from hair cells, including mutations in otoferlin (Pangrsic et al 2010;Roux et al 2006), vesicular glutamate transporter3 (Vglut3) (Seal et al 2008), and Ca v 1.3 (Platzer et al 2000), block activation of spiral ganglion cells by electrical activity both before and after the onset of hearing, whereas those that affect mechanotransduction, including mutations in espin in jerker mice and TMC in deafness mice (Kim et al 2013;Kurima et al 2002), affect activity after the onset of hearing but not before.…”

“…However, electrical activity occurs even before the onset of hearing in auditory circuits; that activity, especially in the second postnatal week, regulates synaptic transmission from hair cells (Beutner and Moser 2001;Johnson et al 2011Johnson et al , 2013Kros et al 1998). Before hearing begins, supporting cells in the cochlea induce action potentials in small groups of adjacent inner hair cells that in turn evoke periodic bursts of suprathreshold responses in the auditory nerve that are propagated to the cortex (Tritsch et al 2007(Tritsch et al , 2010Tritsch and Bergles 2010).…”

L-type calcium channels in the auditory system

“…Fig. 1c); (2) in their role as presynaptic channels, they guarantee that spontaneous IHC activity is conducted to the central auditory pathway; (3) they control expression of genes of the mature IHC [5,15], e.g., expression of the Ca 2+ and voltage-activated K + channel (BK channel) gene. Massive expression of BK channels around day P12 turns off the spontaneous activity phase, permitting the generation of sound-induced graded receptor potentials (.…”