Calcium-Induced Calcium Release during Action Potential Firing in Developing Inner Hair Cells

Abstract

In the mature auditory system, inner hair cells (IHCs) convert sound-induced vibrations into electrical signals that are relayed to the central nervous system via auditory afferents. Before the cochlea can respond to normal sound levels, developing IHCs fire calcium-based action potentials that disappear close to the onset of hearing. Action potential firing triggers transmitter release from the immature IHC that in turn generates experience-independent firing in auditory neurons. These early signaling events are thought to be essential for the organization and development of the auditory system and hair cells. A critical component of the action potential is the rise in intracellular calcium that activates both small conductance potassium channels essential during membrane repolarization, and triggers transmitter release from the cell. Whether this calcium signal is generated by calcium influx or requires calcium-induced calcium release (CICR) is not yet known. IHCs can generate CICR, but to date its physiological role has remained unclear. Here, we used high and low concentrations of ryanodine to block or enhance CICR to determine whether calcium release from intracellular stores affected action potential waveform, interspike interval, or changes in membrane capacitance during development of mouse IHCs. Blocking CICR resulted in mixed action potential waveforms with both brief and prolonged oscillations in membrane potential and intracellular calcium. This mixed behavior is captured well by our mathematical model of IHC electrical activity. We perform two-parameter bifurcation analysis of the model that predicts the dependence of IHCs firing patterns on the level of activation of two parameters, the SK2 channels activation and CICR rate. Our data show that CICR forms an important component of the calcium signal that shapes action potentials and regulates firing patterns, but is not involved directly in triggering exocytosis. These data provide important insights into the calcium signaling mechanisms involved in early developmental processes.

Fast Ca2+ Transients of Inner Hair Cells Arise Coupled and Uncoupled to Ca2+ Waves of Inner Supporting Cells in the Developing Mouse Cochlea

“…Further, Fluo-8 acts as a Ca 2+ buffer itself and could slow the Ca 2+ decay kinetics. The dissociation time constant of the chemically related Fluo-3 is ~5 ms (Eberhard and Erne, 1989 ), much faster than the average decay time of fCaTs of 880 ms. Further, our fCaTs resemble the events measured with simultaneous imaging of Fluo-4FF-filled IHCs and Ca 2+ APs recordings in current clamp (Iosub et al, 2015 ). Taken together, IHC fCaTs imaged under our conditions reflect the Ca 2+ signals resulting from IHC APs.…”

“…In the first postnatal week, mouse and rat IHCs generate Ca 2+ APs that vanish shortly before the onset of hearing (Kros et al, 1998 ; Brandt et al, 2003 , 2007 ; Marcotti et al, 2003b ; Johnson et al, 2005 , 2007 , 2011 , 2012 , 2013 ; Sendin et al, 2014 ; Iosub et al, 2015 ). Ca 2+ APs appear as single events, but more often in bursts of 10–20 single APs.…”

“…It is not surprising that a single fCaT lasts longer than the electrical AP because (i) Ca 2+ influx into an IHC extends to the repolarizing phase of the AP due to the large driving force for Ca 2+ and (ii) AP repolarization by delayed rectifier K + and SK2 channels (Marcotti et al, 2003a ; Mammano and Bortolozzi, 2018 ) is, particularly in minibursts and bursts, faster than clearance of Ca 2+ from the cytosol by Ca 2+ ATPases (Grati et al, 2006 ) or by uptake into intracellular stores and mitochondria (Kennedy, 2002 ), see Figure 3C . Ca 2+ -induced Ca 2+ release from ryanodine-sensitive stores (Iosub et al, 2015 ) may additionally increase and prolong the Ca 2+ signal in IHCs. Further, Fluo-8 acts as a Ca 2+ buffer itself and could slow the Ca 2+ decay kinetics.…”

Fast calcium transients in neuronal spines driven by extreme statistics

“…The timescale generated by the fastest particle or ions is generic and can occur in many molecular transduction pathways where there is a separation between the initial source and a second step that consists of amplifying the signal. This is the case for second 9 messengers such as IP3 [42], G-protein coupled receptors [43] or modulation of the inner hair cell voltage by calcium-induced calcium release [44]. This time scale is very dierent from the Narrow Escape Time [37] phenomena, where the timescale depends on the volume of the domain.…”

Bifurcation analysis of a two-compartment hippocampal pyramidal cell model

“…7 , during the transition between repetitive singlet activity and doublet activity, the V d and C a peaks phase advance but to different extents, leading to a reduction in the ( C a − V d ) phase difference and an increase in the peak which drives the membrane potential to a more hyperpolarised level. This train of events to shift singlet activity to doublet activity seems plausible given changes in , and hence , have previously been shown to shift a cell’s behaviour from spiking to bursting (Tsaneva-Atanasova et al 2007 ; Nowacki et al 2010 ; Szalai et al 2011 ; Iosub et al 2015 ).

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