Mechanisms contributing to synaptic Ca
            <sup>2+</sup>
            signals and their heterogeneity in hair cells

Frank, Tom; Khimich, Darina; Neef, Andreas; Moser, Tobias

doi:10.1073/pnas.0813213106

Cited by 173 publications

(275 citation statements)

References 33 publications

(43 reference statements)

Supporting

Mentioning

241

Contrasting

Order By: Relevance

“…Since ANFs with different spontaneous rates likely innervate the same IHC (Liberman, 1982), the effective local [Ca 2ϩ ] in at individual active zones of a given IHC must differ. In line with this suggestion, Frank et al (2009) and Meyer et al (2009) reported a substantial variability in the magnitude of submicrometer, transient Ca 2ϩ hotspots at the base of individual IHCs. The authors interpret these hotspots as Ca 2ϩ microdomains associated with presynaptic active zones and argue that their variability, which was similar to that of the effective local [Ca 2ϩ ] in estimated here, is due to differences in the number or density of Ca V 1.3 channels near the different ribbon synapses of an individual IHC.…”

supporting

confidence: 51%

An Improved Model for the Rate–Level Functions of Auditory-Nerve Fibers

Heil

Neubauer

Irvine³

2011

J. Neurosci.

View full text Add to dashboard Cite

Acoustic information is conveyed to the brain by the spike patterns in auditory-nerve fibers (ANFs). In mammals, each ANF is excited via a single ribbon synapse in a single inner hair cell (IHC), and the spike patterns therefore also provide valuable information about those intriguing synapses. Here we reexamine and model a key property of ANFs, the dependence of their spike rates on the sound pressure level of acoustic stimuli (rate-level functions). We build upon the seminal model of Sachs and Abbas (1974), which provides good fits to experimental data but has limited utility for defining physiological mechanisms. We present an improved, physiologically plausible model according to which the spike rate follows a Hill equation and spontaneous activity and its experimentally observed tight correlation with ANF sensitivity are emergent properties. We apply it to 156 cat ANF rate-level functions using frequencies where the mechanics are linear and find that a single Hill coefficient of 3 can account for the population of functions. We also demonstrate a tight correspondence between ANF rate-level functions and the Ca 2ϩ dependence of exocytosis from IHCs, and derive estimates of the effective intracellular Ca 2ϩ concentrations at the individual active zones of IHCs. We argue that the Hill coefficient might reflect the intrinsic, biochemical Ca 2ϩ cooperativity of the Ca 2ϩ sensor involved in exocytosis from the IHC. The model also links ANF properties with properties of psychophysical absolute thresholds.

show abstract

supporting

confidence: 51%

An Improved Model for the Rate–Level Functions of Auditory-Nerve Fibers

Heil

Neubauer

Irvine³

2011

J. Neurosci.

View full text Add to dashboard Cite

show abstract

“…S5A; P < 0.002), which is less than the decrease of synaptic Ca V 1.3 immunofluorescence (48%) but exceeds the loss of the whole-cell Ca 2+ current (18%). The fluorescence change varied greatly among the AZs in IHCs of RIM2α SKO mice, as previously described for wild-type IHCs (36). The coefficients of variation were comparable in both genotypes (0.65 for RIM2α con and 0.66 for RIM2α SKO IHCs), again contrasting the synaptic phenotype of Bassoon-deficient IHCs that showed reduced Ca 2+ signaling heterogeneity.…”

Section: Significancementioning

confidence: 66%

“…Neither the single channel current nor the open probability changed significantly (SI Appendix, Table S3). Because the whole-cell recordings sum I Ca of all AZs and extrasynaptic membranes, we sought to further analyze Ca 2+ influx at the single AZ, using confocal Ca 2+ imaging at fluorescently tagged AZs (2,36,37). IHCs were depolarized for 20 ms to −7 mV to fully activate Ca 2+ channels, and Fluo-5N fluorescence was studied using line scans across the center of "Ca 2+ microdomains" ( (Fig.…”

Section: Significancementioning

confidence: 99%

Rab3-interacting molecules 2α and 2β promote the abundance of voltage-gated Ca _V 1.3 Ca ²⁺ channels at hair cell active zones

Jung

Oshima-Takago

Chakrabarti

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

169

View full text Add to dashboard Cite

Ca2+ influx triggers the fusion of synaptic vesicles at the presynaptic active zone (AZ). Here we demonstrate a role of Ras-related in brain 3 (Rab3)-interacting molecules 2α and β (RIM2α and RIM2β) in clustering voltage-gated Ca V 1.3 Ca 2+ channels at the AZs of sensory inner hair cells (IHCs). We show that IHCs of hearing mice express mainly RIM2α, but also RIM2β and RIM3γ, which all localize to the AZs, as shown by immunofluorescence microscopy. Immunohistochemistry, patch-clamp, fluctuation analysis, and confocal Ca 2+ imaging demonstrate that AZs of RIM2α-deficient IHCs cluster fewer synaptic Ca V 1.3 Ca 2+ channels, resulting in reduced synaptic Ca 2+ influx. Using superresolution microscopy, we found that Ca 2+ channels remained clustered in stripes underneath anchored ribbons. Electron tomography of high-pressure frozen synapses revealed a reduced fraction of membrane-tethered vesicles, whereas the total number of membrane-proximal vesicles was unaltered. Membrane capacitance measurements revealed a reduction of exocytosis largely in proportion with the Ca 2+ current, whereas the apparent Ca 2+ dependence of exocytosis was unchanged. Hair cell-specific deletion of all RIM2 isoforms caused a stronger reduction of Ca 2+ influx and exocytosis and significantly impaired the encoding of sound onset in the postsynaptic spiral ganglion neurons. Auditory brainstem responses indicated a mild hearing impairment on hair cell-specific deletion of all RIM2 isoforms or global inactivation of RIM2α. We conclude that RIM2α and RIM2β promote a large complement of synaptic Ca 2+ channels at IHC AZs and are required for normal hearing.ens of Ca V 1.3 Ca 2+ channels are thought to cluster within the active zone (AZ) membrane underneath the presynaptic density of inner hair cells (IHCs) (1-4). They make up the key signaling element, coupling the sound-driven receptor potential to vesicular glutamate release (5-7). The mechanisms governing the number of Ca 2+ channels at the AZ as well as their spatial organization relative to membrane-tethered vesicles are not well understood. Disrupting the presynaptic scaffold protein Bassoon diminishes the numbers of Ca 2+ channels and membrane-tethered vesicles at the AZ (2, 8). However, the loss of Bassoon is accompanied by the loss of the entire synaptic ribbon, which makes it challenging to distinguish the direct effects of gene disruption from secondary effects (9).Among the constituents of the cytomatrix of the AZ, RIM1 and RIM2 proteins are prime candidates for the regulation of Ca 2+ channel clustering and function (10, 11). The family of RIM proteins has seven identified members (RIM1α, RIM1β, RIM2α, RIM2β, RIM2γ, RIM3γ, and RIM4γ) encoded by four genes (RIM1-RIM4). All isoforms contain a C-terminal C 2 domain but differ in the presence of additional domains. RIM1 and RIM2 interact with Ca 2+ channels, most other proteins of the cytomatrix of the AZ, and synaptic vesicle proteins. They interact directly with the auxiliary β (Ca V β) subunits (12, 13) and poreforming Ca V α subun...

show abstract

“…However, differences in spontaneous spike rate among SGNs might not reflect differences in the success rate but rather the rate of release events. EPSC rate heterogeneity might arise from variation between presynaptic Ca 2ϩ microdomains in IHCs (Frank et al, 2009). Our study also suggests, however, that SGNs receiving on average different EPSC waveforms (Grant et al, 2010) would exhibit different spike latencies.…”

Section: Possible Deviations From In Vivo Conditionsmentioning

confidence: 99%

Spike Encoding of Neurotransmitter Release Timing by Spiral Ganglion Neurons of the Cochlea

2012

View full text Add to dashboard Cite

Mammalian cochlear spiral ganglion neurons (SGNs) encode sound with microsecond precision. Spike triggering relies upon input from a single ribbon-type active zone of a presynaptic inner hair cell (IHC). Using patch-clamp recordings of rat SGN postsynaptic boutons innervating the modiolar face of IHCs from the cochlear apex, at room temperature, we studied how spike generation contributes to spike timing relative to synaptic input. SGNs were phasic, firing a single short-latency spike for sustained currents of sufficient onset slope. Almost every EPSP elicited a spike, but latency (300 -1500 s) varied with EPSP size and kinetics. When current-clamp stimuli approximated the mean physiological EPSC (Ϸ300 pA), several times larger than threshold current (rheobase, Ϸ50 pA), spikes were triggered rapidly (latency, Ϸ500 s) and precisely (SD, Ͻ50 s). This demonstrated the significance of strong synaptic input. However, increasing EPSC size beyond the physiological mean resulted in less-potent reduction of latency and jitter. Differences in EPSC charge and SGN baseline potential influenced spike timing less as EPSC onset slope and peak amplitude increased. Moreover, the effect of baseline potential on relative threshold was small due to compensatory shift of absolute threshold potential. Experimental first-spike latencies in response to a broad range of stimuli were predicted by a two-compartment exponential integrate-and-fire model, with latency prediction error of Ͻ100 s. In conclusion, the close anatomical coupling between a strong synapse and spike generator along with the phasic firing property lock SGN spikes to IHC exocytosis timing to generate the auditory temporal code with high fidelity.

show abstract

Mechanisms contributing to synaptic Ca ²⁺ signals and their heterogeneity in hair cells

Cited by 173 publications

References 33 publications

An Improved Model for the Rate–Level Functions of Auditory-Nerve Fibers

An Improved Model for the Rate–Level Functions of Auditory-Nerve Fibers

Rab3-interacting molecules 2α and 2β promote the abundance of voltage-gated Ca _V 1.3 Ca ²⁺ channels at hair cell active zones

Spike Encoding of Neurotransmitter Release Timing by Spiral Ganglion Neurons of the Cochlea

Contact Info

Product

Resources

About

Mechanisms contributing to synaptic Ca 2+ signals and their heterogeneity in hair cells

Cited by 173 publications

References 33 publications

An Improved Model for the Rate–Level Functions of Auditory-Nerve Fibers

An Improved Model for the Rate–Level Functions of Auditory-Nerve Fibers

Rab3-interacting molecules 2α and 2β promote the abundance of voltage-gated Ca V 1.3 Ca 2+ channels at hair cell active zones

Spike Encoding of Neurotransmitter Release Timing by Spiral Ganglion Neurons of the Cochlea

Contact Info

Product

Resources

About

Mechanisms contributing to synaptic Ca ²⁺ signals and their heterogeneity in hair cells

Rab3-interacting molecules 2α and 2β promote the abundance of voltage-gated Ca _V 1.3 Ca ²⁺ channels at hair cell active zones