Biology subjects

Eatock, R. A.

Publications and source records attributed to Eatock, R. A..

7 recordsLinked to original sources

bioRxiv2025

A novel membrane contact site in vestibular hair cells

The mammalian vestibular system has two types of sensory receptor hair cells (HCs), each with different neurotransmission mechanisms. Type II HCs use ribbon synapses to transmit neurotransmitters like glutamate to afferent neurons. On the other hand, type I HCs are nearly engulfed by a calyceal afferent ending and also form ribbon synapses. These HCs regulate afferent activity through non-quantal transmission (NQT), which is faster than classic neurotransmitter release and may play a key role in stabilizing vision and balance during rapid head movements. Here, we describe a novel striated contact, present between the mouse type I HC and its calyceal afferent ending, and intimately associated with atypical plasma membrane-apposed (PMA) mitochondria. This distinctive arrangement has the potential to serve or modulate NQT.

neuroscience↗

bioRxiv2025

KV1.8 (Kcna10) potassium channels enhance fast, linear signaling in vestibular hair cells and facilitate vestibulomotor reflexes and balance

Vestibular hair cells (HCs) faithfully and rapidly detect head motions and gravity, driving motor reflexes that stabilize balance and gaze during locomotion. With the transition from water to land, the amniote vestibular inner ear added type I HCs, which differ from amniote type II HCs and anamniote HCs by their large calyx afferent synapse, non-quantal afferent transmission, and a large, low-voltage-activated K+ conductance (gK,L). We recently showed that both gK,L and the major type II K+ conductances (A-type and delayed rectifier) require KV1.8 (Kcna10) subunits. Here we compared KV1.8-null (Kcna10-/-) and control animals to see how KV1.8 affects function as measured by receptor potentials and nonquantal postsynaptic potentials evoked by direct hair bundle motions, and by vestibulomotor behaviors. Recordings were taken from extrastriolar zones of the utricle. In both HC types, KV1.8 affected receptor potentials by reducing response time and gain, increasing dampening, and expanding the frequency bandwidth toward high frequencies. Effects are most prominent in type I HCs: lowpass corner frequencies of receptor potentials in Kcna10-/- HCs of both types were [~]20 Hz, vs. [~]400 Hz in control type I and [~]70 Hz in control type II. We recorded nonquantal postsynaptic potentials from extrastriolar calyces, and found that the synaptic transfer function had lower gain and greater phase lag in Kcna10-/- mice. In behavioral tests, Kcna10-/- mice had vestibular-ocular reflexes with different response dynamics at low frequencies, impaired performance on a narrow balance beam, abnormal body posture and abnormal head motions in water and on land, and also rarely assumed bipedal stances. These vestibulomotor deficits in Kcna10-/- mice likely reflect the changes noted in HCs, where KV1.8 expression is concentrated; that is, slower signaling of high-frequency head motions by Kcna10-/- HCs fails to fully stabilize body and head position during locomotion. Thus, gK,L (KV1.8) contributes to fast signal transmission in the amniote vestibular inner ear and supports improved performance on challenging vestibulomotor tasks. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=191 SRC="FIGDIR/small/634388v1_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@126570borg.highwire.dtl.DTLVardef@1cab5borg.highwire.dtl.DTLVardef@36240corg.highwire.dtl.DTLVardef@789617_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2024

Contributions of mirror-image hair cell orientation to mouse otolith organ and zebrafish neuromast function

Otolith organs in the inner ear and neuromasts in the fish lateral-line harbor two populations of hair cells oriented to detect stimuli in opposing directions. The underlying mechanism is highly conserved: the transcription factor EMX2 is regionally expressed in just one hair cell population and acts through the receptor GPR156 to reverse cell orientation relative to the other population. In mouse and zebrafish, loss of Emx2 results in sensory organs that harbor only one hair cell orientation and are not innervated properly. In zebrafish, Emx2 also confers hair cells with reduced mechanosensory properties. Here, we leverage mouse and zebrafish models lacking GPR156 to determine how detecting stimuli of opposing directions serves vestibular function, and whether GPR156 has other roles besides orienting hair cells. We find that otolith organs in Gpr156 mouse mutants have normal zonal organization and normal type I-II hair cell distribution and mechano-electrical transduction properties. In contrast, gpr156 zebrafish mutants lack the smaller mechanically-evoked signals that characterize Emx2-positive hair cells. Loss of GPR156 does not affect orientation-selectivity of afferents in mouse utricle or zebrafish neuromasts. Consistent with normal otolith organ anatomy and afferent selectivity, Gpr156 mutant mice do not show overt vestibular dysfunction. Instead, performance on two tests that engage otolith organs is significantly altered - swimming and off-vertical-axis rotation. We conclude that GPR156 relays hair cell orientation and transduction information downstream of EMX2, but not selectivity for direction-specific afferents. These results clarify how molecular mechanisms that confer bi-directionality to sensory organs contribute to function, from single hair cell physiology to animal behavior.

neuroscience↗

bioRxiv2023

Effects of transient, persistent, and resurgent sodium currents on excitability and spike regularity in vestibular ganglion neurons

Vestibular afferent neurons occur as two populations with differences in spike timing regularity that are independent of rate. The more excitable regular afferents have lower current thresholds and sustained spiking responses to injected currents, while irregular afferent neurons have higher thresholds and transient responses. Differences in expression of low-voltage-activated potassium (KLV) channels are emphasized in models of spiking regularity and excitability in these neurons, leaving open the potential contributions of the voltage-gated sodium (NaV) channels responsible for the spike upstroke. We investigated the impact of different NaV current modes (transient, persistent, and resurgent) with whole-cell patch clamp experiments in mouse vestibular ganglion neurons (VGNs), the cultured and dissociated cell bodies of afferents. All VGNs had transient NaV current, many had a small persistent (non-inactivating) NaV current, and a few had resurgent current, which flows after the spike peak when NaV channels that were blocked are unblocked. NaV1.6 channels conducted most or all of each NaV current mode, and a NaV1.6-selective blocker decreased spike rate and altered spike waveforms in both sustained and transient VGNs. A NaV channel agonist enhanced persistent current and increased spike rate and regularity. We hypothesized that persistent and resurgent currents have different effects on sustained (regular) VGNs vs. transient (irregular) VGNs. Lacking blockers specific for the different current modes, we used modeling to isolate their effects on spiking of simulated transient and sustained VGNs, driven by simulated current steps and noisy trains of simulated EPSCs. In all simulated neurons, increasing transient NaV current increased spike rate and rate-independent regularity. In simulated sustained VGNs, adding persistent current increased both rate and rate-independent regularity, while adding resurgent current had limited impact. In transient VGNs, adding persistent current had little impact, while adding resurgent current increased both rate and rate-independent irregularity by enhancing sensitivity to synaptic noise. These experiments show that the small NaV current modes may enhance the differentiation of afferent populations, with persistent currents selectively making regular afferents more regular and resurgent currents selectively making irregular afferents less regular.

neuroscience↗

bioRxiv2023

The potassium channel subunit KV1.8 (Kcna10) is essential for the distinctive outwardly rectifying conductances of type I and II vestibular hair cells

In amniotes, head motions and tilt are detected by two types of vestibular hair cells (HCs) with strikingly different morphology and physiology. Mature type I HCs express a large and very unusual potassium conductance, gK,L, which activates negative to resting potential, confers very negative resting potentials and low input resistances, and enhances an unusual non-quantal transmission from type I cells onto their calyceal afferent terminals. Following clues pointing to KV1.8 (KCNA10) in the Shaker K channel family as a candidate gK,L subunit, we compared whole-cell voltage-dependent currents from utricular hair cells of KV1.8-null mice and littermate controls. We found that KV1.8 is necessary not just for gK,L but also for fast-inactivating and delayed rectifier currents in type II HCs, which activate positive to resting potential. The distinct properties of the three KV1.8-dependent conductances may reflect different mixing with other KV subunits that are reported to be differentially expressed in type I and II HCs. In KV1.8-null HCs of both types, residual outwardly rectifying conductances include KV7 (KCNQ) channels. Current clamp records show that in both HC types, KV1.8-dependent conductances increase the speed and damping of voltage responses. Features that speed up vestibular receptor potentials and non-quantal afferent transmission may have helped stabilize locomotion as tetrapods moved from water to land. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=138 SRC="FIGDIR/small/563853v3_ufig1.gif" ALT="Figure 1"> View larger version (20K): org.highwire.dtl.DTLVardef@1409188org.highwire.dtl.DTLVardef@12aaa0org.highwire.dtl.DTLVardef@18000e0org.highwire.dtl.DTLVardef@b995c5_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2021

A Biophysical Model of Nonquantal Transmission at the Vestibular Hair Cell-Calyx Synapse: KLV currents Modulate Fast Electrical and Slow K+ potentials in the Synaptic Cleft

Vestibular hair cells transmit information about head position and motion across synapses to primary afferent neurons. At some of these synapses, the afferent neuron envelopes the hair cell, forming an enlarged synaptic terminal called a calyx. The vestibular hair cell-calyx synapse supports a mysterious form of electrical transmission that does not involve gap junctions termed nonquantal transmission (NQT). The NQT mechanism is thought to involve the flow of ions from the pre-synaptic hair cell to the post-synaptic calyx through low-voltage-activated channels driven by changes in cleft [K+] as K+ exits the hair cell. However, this hypothesis has not been tested with a quantitative model and the possible role of an electrical potential in the cleft has remained speculative. Here we present a computational model that captures salient experimental observations of NQT and identifies overlooked features that corroborate the existence of an electrical potential ({phi}) in the synaptic cleft. We show that changes in cleft{phi} reduce transmission latency and illustrate the relative contributions of both cleft [K+] and{phi} to the gain and phase of NQT. We further demonstrate that the magnitude and speed of NQT depend on calyx morphology and that increasing calyx height reduces action potential latency in the calyx afferent. These predictions are consistent with the idea that the calyx evolved to enhance NQT and speed up vestibular signals that drive neural circuits controlling gaze, balance, and orientation. Significance StatementThe ability of the vestibular system to drive the fastest reflexes in the nervous system depends on rapid transmission of mechanosensory signals at vestibular hair cell synapses. In mammals and other amniotes, afferent neurons form unusually large calyx terminals on certain hair cells, and communication at these synapses includes nonquantal transmission (NQT), which avoids the synaptic delay of quantal transmission. We present a quantitative model that shows how NQT depends on the extent of the calyx covering the hair cell and attributes the short latency of NQT to changes in synaptic cleft electrical potential caused by current flowing through open potassium channels in the hair cell. This previously undescribed mechanism may act at other synapses.

neuroscience↗

bioRxiv2019

Cytochrome P450 26b1-mediated specification of vestibular striola and central zones is required for transient responses in linear acceleration

Each vestibular sensory epithelia of the inner ear is divided into two zones, the striola and extrastriola in maculae of otolith organs and the central and peripheral zones in cristae of semicircular canals, that differ in morphology and physiology. We found that formation of striolar/central zones during embryogenesis requires Cytochrome P450 26b1 (Cyp26b1)-mediated degradation of retinoic acid (RA). In Cyp26b1 conditional knockout mice, the identities of the striolar/central zones were compromised, including abnormal innervating neurons and otoconia in otolith organs. Vestibular evoked potentials (VsEP) in response to jerk stimuli were largely absent. Vestibulo-ocular reflexes and standard motor performances such as forced swimming were unaffected, but mutants had head tremors and deficits in balance beam tests that were consistent with abnormal vestibular input. Thus, degradation of RA during embryogenesis is required for patterning highly specialized regions of the vestibular sensory epithelia that may provide acute feedback about head motion.

neuroscience↗