The Experts below are selected from a list of 2754 Experts worldwide ranked by ideXlab platform

Alaa Koleilat - One of the best experts on this subject based on the ideXlab platform.

  • l type voltage gated calcium channel agonists mitigate hearing loss and modify Ribbon Synapse morphology in the zebrafish model of usher syndrome type 1
    Disease Models & Mechanisms, 2020
    Co-Authors: Alaa Koleilat, Joseph A Dugdale, Trace A Christenson, Jeffrey L Bellah, Aaron M Lambert, Mark A Masino, Stephen C Ekker
    Abstract:

    ABSTRACT The mariner (myo7aa−/−) mutant is a zebrafish model for Usher syndrome type 1 (USH1). To further characterize hair cell synaptic elements in myo7aa−/− mutants, we focused on the Ribbon Synapse and evaluated ultrastructure, number and distribution of immunolabeled Ribbons, and postsynaptic densities. By transmission electron microscopy, we determined that myo7aa−/− zebrafish have fewer glutamatergic vesicles tethered to Ribbon Synapses, yet maintain a comparable Ribbon area. In myo7aa−/− hair cells, immunolocalization of Ctbp2 showed fewer Ribbon-containing cells in total and an altered distribution of Ctbp2 puncta compared to wild-type hair cells. myo7aa−/− mutants have fewer postsynaptic densities – as assessed by MAGUK immunolabeling – compared to wild-type zebrafish. We quantified the circular swimming behavior of myo7aa−/− mutant fish and measured a greater turning angle (absolute smooth orientation). It has previously been shown that L-type voltage-gated calcium channels are necessary for Ribbon localization and occurrence of postsynaptic density; thus, we hypothesized and observed that L-type voltage-gated calcium channel agonists change behavioral and synaptic phenotypes in myo7aa−/− mutants in a drug-specific manner. Our results indicate that treatment with L-type voltage-gated calcium channel agonists alter hair cell synaptic elements and improve behavioral phenotypes of myo7aa−/− mutants. Our data support that L-type voltage-gated calcium channel agonists induce morphological changes at the Ribbon Synapse – in both the number of tethered vesicles and regarding the distribution of Ctbp2 puncta – shift swimming behavior and improve acoustic startle response.

  • l type voltage gated calcium channel agonists improve hearing loss and modify Ribbon Synapse morphology in the zebrafish model of usher syndrome type 1
    bioRxiv, 2019
    Co-Authors: Alaa Koleilat, Joseph A Dugdale, Trace A Christenson, Jeffrey L Bellah, Aaron M Lambert, Mark A Masino, Stephen C Ekker, Lisa A Schimmenti
    Abstract:

    Usher Syndrome (USH) is the most common cause of human deaf/blindness. The zebrafish myo7aa homozygous mutant, faithfully models USH1; homozygous zebrafish are deaf and exhibit circular swimming. We hypothesized that hair cell morphology would differ in myo7aa homozygous mutants compared to wild type. We also tested the hypothesis that agonists of L type voltage gated calcium channels would alter Ribbon Synapse morphology and behavior of zebrafish myo7aa homozygous mutants. We discovered that myo7aa homozygous mutant zebrafish have fewer glutamatergic vesicles tethered to hair cell Ribbon Synapses, yet maintain a comparable Ribbon area. We identified that myo7aa homozygous mutants have fewer total active hair cells, fewer total CTBP2 expressing puncta, and an altered distribution of CTBP2 puncta compared to wildtype. We also identified that myo7aa homozygous mutants have fewer active postsynaptic cells and fewer total MAGUK puncta, compared to wildtype. Behaviorally, myo7aa homozygous mutant fish have abnormal swimming as measured by larger absolute smooth orientations and have little to no acoustic startle. Treatment with L type voltage gated calcium channel agonists altered the abnormal cell and behavioral phenotypes toward wildtype. Our data supports that L type voltage gated calcium channel agonists induce morphological changes at the Ribbon Synapse, in both the number of tethered vesicles and the distribution of CTBP2 puncta, shifts swimming behavior towards wildtype swimming and improves acoustic startle response.

Stephen C Ekker - One of the best experts on this subject based on the ideXlab platform.

  • l type voltage gated calcium channel agonists mitigate hearing loss and modify Ribbon Synapse morphology in the zebrafish model of usher syndrome type 1
    Disease Models & Mechanisms, 2020
    Co-Authors: Alaa Koleilat, Joseph A Dugdale, Trace A Christenson, Jeffrey L Bellah, Aaron M Lambert, Mark A Masino, Stephen C Ekker
    Abstract:

    ABSTRACT The mariner (myo7aa−/−) mutant is a zebrafish model for Usher syndrome type 1 (USH1). To further characterize hair cell synaptic elements in myo7aa−/− mutants, we focused on the Ribbon Synapse and evaluated ultrastructure, number and distribution of immunolabeled Ribbons, and postsynaptic densities. By transmission electron microscopy, we determined that myo7aa−/− zebrafish have fewer glutamatergic vesicles tethered to Ribbon Synapses, yet maintain a comparable Ribbon area. In myo7aa−/− hair cells, immunolocalization of Ctbp2 showed fewer Ribbon-containing cells in total and an altered distribution of Ctbp2 puncta compared to wild-type hair cells. myo7aa−/− mutants have fewer postsynaptic densities – as assessed by MAGUK immunolabeling – compared to wild-type zebrafish. We quantified the circular swimming behavior of myo7aa−/− mutant fish and measured a greater turning angle (absolute smooth orientation). It has previously been shown that L-type voltage-gated calcium channels are necessary for Ribbon localization and occurrence of postsynaptic density; thus, we hypothesized and observed that L-type voltage-gated calcium channel agonists change behavioral and synaptic phenotypes in myo7aa−/− mutants in a drug-specific manner. Our results indicate that treatment with L-type voltage-gated calcium channel agonists alter hair cell synaptic elements and improve behavioral phenotypes of myo7aa−/− mutants. Our data support that L-type voltage-gated calcium channel agonists induce morphological changes at the Ribbon Synapse – in both the number of tethered vesicles and regarding the distribution of Ctbp2 puncta – shift swimming behavior and improve acoustic startle response.

  • l type voltage gated calcium channel agonists improve hearing loss and modify Ribbon Synapse morphology in the zebrafish model of usher syndrome type 1
    bioRxiv, 2019
    Co-Authors: Alaa Koleilat, Joseph A Dugdale, Trace A Christenson, Jeffrey L Bellah, Aaron M Lambert, Mark A Masino, Stephen C Ekker, Lisa A Schimmenti
    Abstract:

    Usher Syndrome (USH) is the most common cause of human deaf/blindness. The zebrafish myo7aa homozygous mutant, faithfully models USH1; homozygous zebrafish are deaf and exhibit circular swimming. We hypothesized that hair cell morphology would differ in myo7aa homozygous mutants compared to wild type. We also tested the hypothesis that agonists of L type voltage gated calcium channels would alter Ribbon Synapse morphology and behavior of zebrafish myo7aa homozygous mutants. We discovered that myo7aa homozygous mutant zebrafish have fewer glutamatergic vesicles tethered to hair cell Ribbon Synapses, yet maintain a comparable Ribbon area. We identified that myo7aa homozygous mutants have fewer total active hair cells, fewer total CTBP2 expressing puncta, and an altered distribution of CTBP2 puncta compared to wildtype. We also identified that myo7aa homozygous mutants have fewer active postsynaptic cells and fewer total MAGUK puncta, compared to wildtype. Behaviorally, myo7aa homozygous mutant fish have abnormal swimming as measured by larger absolute smooth orientations and have little to no acoustic startle. Treatment with L type voltage gated calcium channel agonists altered the abnormal cell and behavioral phenotypes toward wildtype. Our data supports that L type voltage gated calcium channel agonists induce morphological changes at the Ribbon Synapse, in both the number of tethered vesicles and the distribution of CTBP2 puncta, shifts swimming behavior towards wildtype swimming and improves acoustic startle response.

Jeffrey L Bellah - One of the best experts on this subject based on the ideXlab platform.

  • l type voltage gated calcium channel agonists mitigate hearing loss and modify Ribbon Synapse morphology in the zebrafish model of usher syndrome type 1
    Disease Models & Mechanisms, 2020
    Co-Authors: Alaa Koleilat, Joseph A Dugdale, Trace A Christenson, Jeffrey L Bellah, Aaron M Lambert, Mark A Masino, Stephen C Ekker
    Abstract:

    ABSTRACT The mariner (myo7aa−/−) mutant is a zebrafish model for Usher syndrome type 1 (USH1). To further characterize hair cell synaptic elements in myo7aa−/− mutants, we focused on the Ribbon Synapse and evaluated ultrastructure, number and distribution of immunolabeled Ribbons, and postsynaptic densities. By transmission electron microscopy, we determined that myo7aa−/− zebrafish have fewer glutamatergic vesicles tethered to Ribbon Synapses, yet maintain a comparable Ribbon area. In myo7aa−/− hair cells, immunolocalization of Ctbp2 showed fewer Ribbon-containing cells in total and an altered distribution of Ctbp2 puncta compared to wild-type hair cells. myo7aa−/− mutants have fewer postsynaptic densities – as assessed by MAGUK immunolabeling – compared to wild-type zebrafish. We quantified the circular swimming behavior of myo7aa−/− mutant fish and measured a greater turning angle (absolute smooth orientation). It has previously been shown that L-type voltage-gated calcium channels are necessary for Ribbon localization and occurrence of postsynaptic density; thus, we hypothesized and observed that L-type voltage-gated calcium channel agonists change behavioral and synaptic phenotypes in myo7aa−/− mutants in a drug-specific manner. Our results indicate that treatment with L-type voltage-gated calcium channel agonists alter hair cell synaptic elements and improve behavioral phenotypes of myo7aa−/− mutants. Our data support that L-type voltage-gated calcium channel agonists induce morphological changes at the Ribbon Synapse – in both the number of tethered vesicles and regarding the distribution of Ctbp2 puncta – shift swimming behavior and improve acoustic startle response.

  • l type voltage gated calcium channel agonists improve hearing loss and modify Ribbon Synapse morphology in the zebrafish model of usher syndrome type 1
    bioRxiv, 2019
    Co-Authors: Alaa Koleilat, Joseph A Dugdale, Trace A Christenson, Jeffrey L Bellah, Aaron M Lambert, Mark A Masino, Stephen C Ekker, Lisa A Schimmenti
    Abstract:

    Usher Syndrome (USH) is the most common cause of human deaf/blindness. The zebrafish myo7aa homozygous mutant, faithfully models USH1; homozygous zebrafish are deaf and exhibit circular swimming. We hypothesized that hair cell morphology would differ in myo7aa homozygous mutants compared to wild type. We also tested the hypothesis that agonists of L type voltage gated calcium channels would alter Ribbon Synapse morphology and behavior of zebrafish myo7aa homozygous mutants. We discovered that myo7aa homozygous mutant zebrafish have fewer glutamatergic vesicles tethered to hair cell Ribbon Synapses, yet maintain a comparable Ribbon area. We identified that myo7aa homozygous mutants have fewer total active hair cells, fewer total CTBP2 expressing puncta, and an altered distribution of CTBP2 puncta compared to wildtype. We also identified that myo7aa homozygous mutants have fewer active postsynaptic cells and fewer total MAGUK puncta, compared to wildtype. Behaviorally, myo7aa homozygous mutant fish have abnormal swimming as measured by larger absolute smooth orientations and have little to no acoustic startle. Treatment with L type voltage gated calcium channel agonists altered the abnormal cell and behavioral phenotypes toward wildtype. Our data supports that L type voltage gated calcium channel agonists induce morphological changes at the Ribbon Synapse, in both the number of tethered vesicles and the distribution of CTBP2 puncta, shifts swimming behavior towards wildtype swimming and improves acoustic startle response.

Aaron M Lambert - One of the best experts on this subject based on the ideXlab platform.

  • l type voltage gated calcium channel agonists mitigate hearing loss and modify Ribbon Synapse morphology in the zebrafish model of usher syndrome type 1
    Disease Models & Mechanisms, 2020
    Co-Authors: Alaa Koleilat, Joseph A Dugdale, Trace A Christenson, Jeffrey L Bellah, Aaron M Lambert, Mark A Masino, Stephen C Ekker
    Abstract:

    ABSTRACT The mariner (myo7aa−/−) mutant is a zebrafish model for Usher syndrome type 1 (USH1). To further characterize hair cell synaptic elements in myo7aa−/− mutants, we focused on the Ribbon Synapse and evaluated ultrastructure, number and distribution of immunolabeled Ribbons, and postsynaptic densities. By transmission electron microscopy, we determined that myo7aa−/− zebrafish have fewer glutamatergic vesicles tethered to Ribbon Synapses, yet maintain a comparable Ribbon area. In myo7aa−/− hair cells, immunolocalization of Ctbp2 showed fewer Ribbon-containing cells in total and an altered distribution of Ctbp2 puncta compared to wild-type hair cells. myo7aa−/− mutants have fewer postsynaptic densities – as assessed by MAGUK immunolabeling – compared to wild-type zebrafish. We quantified the circular swimming behavior of myo7aa−/− mutant fish and measured a greater turning angle (absolute smooth orientation). It has previously been shown that L-type voltage-gated calcium channels are necessary for Ribbon localization and occurrence of postsynaptic density; thus, we hypothesized and observed that L-type voltage-gated calcium channel agonists change behavioral and synaptic phenotypes in myo7aa−/− mutants in a drug-specific manner. Our results indicate that treatment with L-type voltage-gated calcium channel agonists alter hair cell synaptic elements and improve behavioral phenotypes of myo7aa−/− mutants. Our data support that L-type voltage-gated calcium channel agonists induce morphological changes at the Ribbon Synapse – in both the number of tethered vesicles and regarding the distribution of Ctbp2 puncta – shift swimming behavior and improve acoustic startle response.

  • l type voltage gated calcium channel agonists improve hearing loss and modify Ribbon Synapse morphology in the zebrafish model of usher syndrome type 1
    bioRxiv, 2019
    Co-Authors: Alaa Koleilat, Joseph A Dugdale, Trace A Christenson, Jeffrey L Bellah, Aaron M Lambert, Mark A Masino, Stephen C Ekker, Lisa A Schimmenti
    Abstract:

    Usher Syndrome (USH) is the most common cause of human deaf/blindness. The zebrafish myo7aa homozygous mutant, faithfully models USH1; homozygous zebrafish are deaf and exhibit circular swimming. We hypothesized that hair cell morphology would differ in myo7aa homozygous mutants compared to wild type. We also tested the hypothesis that agonists of L type voltage gated calcium channels would alter Ribbon Synapse morphology and behavior of zebrafish myo7aa homozygous mutants. We discovered that myo7aa homozygous mutant zebrafish have fewer glutamatergic vesicles tethered to hair cell Ribbon Synapses, yet maintain a comparable Ribbon area. We identified that myo7aa homozygous mutants have fewer total active hair cells, fewer total CTBP2 expressing puncta, and an altered distribution of CTBP2 puncta compared to wildtype. We also identified that myo7aa homozygous mutants have fewer active postsynaptic cells and fewer total MAGUK puncta, compared to wildtype. Behaviorally, myo7aa homozygous mutant fish have abnormal swimming as measured by larger absolute smooth orientations and have little to no acoustic startle. Treatment with L type voltage gated calcium channel agonists altered the abnormal cell and behavioral phenotypes toward wildtype. Our data supports that L type voltage gated calcium channel agonists induce morphological changes at the Ribbon Synapse, in both the number of tethered vesicles and the distribution of CTBP2 puncta, shifts swimming behavior towards wildtype swimming and improves acoustic startle response.

Elisabeth Glowatzki - One of the best experts on this subject based on the ideXlab platform.

  • Video Article Postsynaptic Recordings at Afferent Dendrites Contacting Cochlear Inner Hair Cells: Monitoring Multivesicular Release at a Ribbon Synapse
    2016
    Co-Authors: Lisa Grant, Juan D. Goutman, Elisabeth Glowatzki
    Abstract:

    The afferent Synapse between the inner hair cell (IHC) and the auditory nerve fiber provides an electrophysiologically accessible site for recording the postsynaptic activity of a single Ribbon Synapse 1-4. Ribbon Synapses of sensory cells release neurotransmitter continuously, the rate of which is modulated in response to graded changes in IHC membrane potential 5. Ribbon Synapses have been shown to operate by multivesicular release, where multiple vesicles can be released simultaneously to evoke excitatory postsynaptic currents (EPSCs) of varying amplitudes 1, 4, 6-11. Neither the role of the presynaptic Ribbon, nor the mechanism underlying multivesicular release is currently well understood. The IHC is innervated by 10-20 auditory nerve fibers, and every fiber contacts the IHC with a unmyelinated single ending to form a single Ribbon Synapse. The small size of the afferent boutons contacting IHCs (approximately 1 μm in diameter) enables recordings with exceptional temporal resolution to be made. Furthermore, the technique can be adapted to record from both pre- and postsynaptic cells simultaneously

  • Hair Cell Ribbon Synapse Function - Differently Optimized for Hearing and Balance
    Biophysical Journal, 2015
    Co-Authors: Soroush G. Sadeghi, Sonja J. Pyott, Elisabeth Glowatzki
    Abstract:

    In the cochlea, inner hair cells transmit the sound signal via type I auditory nerve fibers to the brain, and outer hair cells mainly operate as local amplifiers of the sound signal in the periphery. However, outer hair cells also contact a small group of afferent type II fibers, of unknown function. In the vestibular organs in the inner ear, hair cells transmit head rotation signals to the brain, via vestibular nerve fibers. All of these different hair cell types release glutamate onto their afferent contacts via Ribbon Synapses. Interestingly, synaptic transmission at these individual hair cell Ribbon Synapses operates differently in many respects, most likely optimized for their specific function.For example, at the inner hair cell Synapse, known for its high reliability and precision, EPSC are fast and amplitudes are quite variable in size and unusually large, with distributions from 20 pA to 1 nA (holding potential −94 mV). In comparison, at outer and vestibular type I hair cells, EPSCs show rather ‘conventional’ sizes of 20 - 50 pA. At inner hair cell Ribbon Synapses, EPSC amplitude distributions are quite diverse for individual nerve fibers, and we propose that specific distributions underlie ‘high’ and ‘low spontaneous rate fibers carrying different aspects of the sound signal. Interestingly, EPSC distributions are calcium-independent, as hair cell depolarizations do not change the distributions. At the vestibular type I hair cell afferent Synapse, hair cell depolarization shifts the amplitude distribution, suggesting a calcium-dependence. Postsynaptically, EPSCs are unusually slow, causing slow, summed depolarizations of the postsynaptic membrane and thereby a change in firing rate.In summary, different mechanisms of Ribbon Synapse transmission and their function at different hair cells will be compared and discussed.Supported by NIDCD R01DC006476 and R01DC012957 to EG.

  • short term facilitation modulates size and timing of the synaptic response at the inner hair cell Ribbon Synapse
    The Journal of Neuroscience, 2011
    Co-Authors: Juan D. Goutman, Elisabeth Glowatzki
    Abstract:

    Inner hair cells (IHCs) in the mammalian cochlea are able to continuously release neurotransmitter in the presence of constant stimuli. Nonetheless, strong synaptic depression is observed over the first few milliseconds of stimulation. This process most likely underlies adaptation in the auditory nerve. In the present study we demonstrate that under certain conditions of stimulation, facilitation can occur at the IHC Ribbon Synapse. Using simultaneous whole-cell, voltage-clamp recordings from IHCs and afferent fiber endings in excised postnatal rat cochleae, we stimulated IHCs with 2 ms long test depolarizations from a holding potential of -89 mV. Synaptic currents in afferent fibers occurred with high failure rates of ∼ 50%. However, when a pre-depolarization to values of -55 to -49 mV was implemented before the test pulse, success rates of the synaptic response increased to 100%, the strength of the synaptic response increased ∼ 2.8-fold, and synaptic latency was reduced by ∼ 50%. When calcium influx was minimized during pre-depolarization, none of these effects were found, suggesting that calcium influx during pre-depolarizations is required for synaptic conditioning. Similarly, in response to paired-pulse protocols, short term facilitation occurred. The response to the second stimulus increased up to ∼ 5-fold, and its latency was reduced by up to 35% compared to the response to the first stimulus. We propose that at the IHC resting membrane potential, the Ribbon Synapse operates in a constantly facilitated mode caused by Ca(2+) influx, optimizing the size and timing of the postsynaptic response in auditory nerve fibers.

  • Postsynaptic Recordings at Afferent Dendrites Contacting Cochlear Inner Hair Cells: Monitoring Multivesicular Release at a Ribbon Synapse
    Journal of visualized experiments : JoVE, 2011
    Co-Authors: Lisa Grant, Juan D. Goutman, Elisabeth Glowatzki
    Abstract:

    The afferent Synapse between the inner hair cell (IHC) and the auditory nerve fiber provides an electrophysiologically accessible site for recording the postsynaptic activity of a single Ribbon Synapse 1-4 . Ribbon Synapses of sensory cells release neurotransmitter continuously, the rate of which is modulated in response to graded changes in IHC membrane potential 5 . Ribbon Synapses have been shown to operate by multivesicular release, where multiple vesicles can be released simultaneously to evoke excitatory postsynaptic currents (EPSCs) of varying amplitudes 1, 4, 6-11 . Neither the role of the presynaptic Ribbon, nor the mechanism underlying multivesicular release is currently well understood.

  • time course and calcium dependence of transmitter release at a single Ribbon Synapse
    Proceedings of the National Academy of Sciences of the United States of America, 2007
    Co-Authors: Juan D. Goutman, Elisabeth Glowatzki
    Abstract:

    At the first Synapse in the auditory pathway, the receptor potential of mechanosensory hair cells is converted into a firing pattern in auditory nerve fibers. For the accurate coding of timing and intensity of sound signals, transmitter release at this Synapse must occur with the highest precision. To measure directly the transfer characteristics of the hair cell afferent Synapse, we implemented simultaneous whole-cell recordings from mammalian inner hair cells (IHCs) and auditory nerve fiber terminals that typically receive input from a single Ribbon Synapse. During a 1-s IHC depolarization, the synaptic response depressed >90%, representing the main source for adaptation in the auditory nerve. Synaptic depression was slightly affected by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor desensitization; however, it was mostly caused by reduced vesicular release. When the transfer function between transmitter release and Ca2+ influx was tested at constant open probability for Ca2+ channels (potentials >0 mV), a super linear relation was found. This relation is presumed to result from the cooperative binding of three to four Ca2+ ions at the Ca2+ sensor. However, in the physiological range for receptor potentials (−50 to −30 mV), the relation between Ca2+ influx and afferent activity was linear, assuring minimal distortion in the coding of sound intensity. Changes in Ca2+ influx caused an increase in release probability, but not in the average size of multivesicular synaptic events. By varying Ca2+ buffering in the IHC, we further investigate how Ca2+ channel and Ca2+ sensor at this Synapse might relate.