Paul A Fuchs

Johns Hopkins Medicine, Baltimore, MD, United States

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Publications (53)386.9 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Two types of sensory hair cells in the mammalian cochlea signal through anatomically distinct populations of spiral ganglion afferent neurons. The solitary inner hair cell ribbon synapse uses multivesicular release to trigger action potentials that encode acoustic timing, intensity, and frequency in each type I afferent. In contrast, cochlear outer hair cells (OHCs) have a far weaker effect on their postsynaptic targets, the type II spiral ganglion afferents. OHCs typically release single vesicles with low probability so that extensive summation is required to reach the relatively high action potential initiation threshold. These stark differences in synaptic transfer call into question whether type II neurons contribute to the cognitive perception of sound. Given the sparse and weak synaptic inputs from OHCs, the electrical properties of type II afferents are crucial in determining whether synaptic responses can sum to evoke an action potential to convey information to the cochlear nucleus. In the present work, dual-electrode recordings determined that type II afferents of rats have length constants that exceed the length of the distal, spiral process, enabling spatial summation from widespread OHCs. Focal application of tetrodotoxin localized the spike initiation zone to the type II proximal, radial process, near the spiral ganglion, in agreement with the high voltage threshold measured in the spiral process. These measured membrane properties were incorporated into a compartmental model of the type II neuron to demonstrate that neurotransmitter release from at least six OHCs is required to trigger an action potential in a type II neuron.
    Journal of Neuroscience 02/2014; 34(6):2365-73. · 6.91 Impact Factor
  • Paul Albert Fuchs, Mohamed Lehar, Hakim Hiel
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    ABSTRACT: 'C' (cisternal) synapses with a near membrane postsynaptic cistern are found on motor neurons and other central neurons where their functional role is unknown. Similarly structured cisternal synapses mediate cholinergic inhibition of cochlear hair cells via α9α10-containing ionotropic receptors and associated calcium-activated (SK2) potassium channels, providing the opportunity to examine the ultrastructure of genetically-altered cisternal synapses. Serial section electron microscopy was used to examine efferent synapses of outer hair cells (OHCs) in mice with diminished or enhanced cholinergic inhibition. The contact area of efferent terminals, the appositional area of the postsynaptic cistern, the distance of the cistern from the plasma membrane, and the average width of the cisternal lumen were recorded. The synaptic cisterns of wildtype OHCs were closely aligned (14 nm separation) with the hair cell membrane and co-extensive with the micrometers-long synaptic terminals. The cisternal lumen averaged 18 nm so that the cisternal volume was approximately 30% larger than that of the cytoplasmic space between the cistern and the plasma membrane. Synaptic ultrastructure of α9L9'T knock-in OHCs ('AChR gain of function') were like those of wildtype littermates except that cisternal volumes were significantly larger. OHCs of SK2 knockout mice had few small efferent terminals. Synaptic cisterns were present, but smaller than those of wildtype littermates. Taken together, these data suggest that the cistern serves as a sink or buffer to isolate synaptic calcium signals. J. Comp. Neurol., 2013. © 2013 Wiley Periodicals, Inc.
    The Journal of Comparative Neurology 10/2013; · 3.66 Impact Factor
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    ABSTRACT: The synapse between olivocochlear (OC) neurons and cochlear mechanosensory hair cells is cholinergic, fast, and inhibitory. The inhibitory sign of this cholinergic synapse is accounted for by the activation of Ca(2+)-permeable postsynaptic α9α10 nicotinic receptors coupled to the opening of hyperpolarizing Ca(2+)-activated small-conductance type 2 (SK2)K(+) channels. Acetylcholine (ACh) release at this synapse is supported by both P/Q- and N-type voltage-gated calcium channels (VGCCs). Although the OC synapse is cholinergic, an abundant OC GABA innervation is present along the mammalian cochlea. The role of this neurotransmitter at the OC efferent innervation, however, is for the most part unknown. We show that GABA fails to evoke fast postsynaptic inhibitory currents in apical developing inner and outer hair cells. However, electrical stimulation of OC efferent fibers activates presynaptic GABAB(1a,2) receptors [GABAB(1a,2)Rs] that downregulate the amount of ACh released at the OC-hair cell synapse, by inhibiting P/Q-type VGCCs. We confirmed the expression of GABABRs at OC terminals contacting the hair cells by coimmunostaining for GFP and synaptophysin in transgenic mice expressing GABAB1-GFP fusion proteins. Moreover, coimmunostaining with antibodies against the GABA synthetic enzyme glutamic acid decarboxylase and synaptophysin support the idea that GABA is directly synthesized at OC terminals contacting the hair cells during development. Thus, we demonstrate for the first time a physiological role for GABA in cochlear synaptic function. In addition, our data suggest that the GABAB1a isoform selectively inhibits release at efferent cholinergic synapses.
    Journal of Neuroscience 09/2013; 33(39):15477-15487. · 6.91 Impact Factor
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    ABSTRACT: Cochlear inner hair cells (IHCs) are temporarily innervated by efferent cholinergic fibers prior to the onset of hearing. During low-frequency firing, these efferent synapses have a relatively low probability of transmitter release but facilitate strongly with repetitive stimulation. A retrograde signal from the hair cell to the efferent terminal contributes to this facilitation. When IHCs were treated with the ryanodine receptor agonist, cyclic adenosine phosphoribose (cADPR), release probability of the efferent terminal rose. This effect was quantified by computing the quantum content from a train of 100 suprathreshold stimuli to the efferent fibers. Quantum content was sevenfold higher when IHCs were treated with 100 μM cADPR (applied in the recording pipette). Since cADPR is membrane impermeant, this result implies that an extracellular messenger travels from the hair cell to the efferent terminal. cADPR is presumed to generate this messenger by increasing cytoplasmic calcium. Consistent with this presumption, voltage-gated calcium flux into the IHC also caused retrograde facilitation of efferent transmission. Retrograde facilitation was observed in IHCs of a vesicular glutamate transporter (VGlut3) null mouse and for wild-type rat hair cells subject to wide-spectrum glutamate receptor blockade, demonstrating that glutamate was unlikely to be the extracellular messenger. Rather, bath application of nitric oxide (NO) donors caused an increase in potassium-evoked efferent transmitter release while the NO scavenger carboxy-PTIO was able to prevent retrograde facilitation produced by cADPR or IHC depolarization. Thus, hair cell activity can drive retrograde facilitation of efferent input via calcium-dependent production of NO.
    Journal of the Association for Research in Otolaryngology 11/2012; · 2.95 Impact Factor
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    ABSTRACT: Type II cochlear afferents receive glutamatergic synaptic excitation from outer hair cells (OHCs) in the rat cochlea. However, it remains uncertain whether this connection is capable of providing auditory information to the brain. The functional efficacy of this connection depends in part on the number of presynaptic OHCs, their probability of transmitter release, and the effective electrical distance for spatial summation in the type II fiber. The present work addresses these questions using whole-cell recordings from the spiral process of type II afferents that run below OHCs in the apical turn of young (5-9 d postnatal) rat cochlea. A "high potassium puffer" was used to elicit calcium action potentials from individual OHCs and thereby show that the average probability of transmitter release was 0.26 (range 0.02-0.73). Electron microscopy showed relatively few vesicles tethered to ribbons in equivalent OHCs. A "receptive field" map for individual type II fibers was constructed by successively puffing onto OHCs along the cochlear spiral, up to 180 μm from the recording pipette. These revealed a conservative estimate of 7 presynaptic OHCs per type II fiber (range 1-11). EPSCs evoked from presynaptic OHCs separated by >100 μm did not differ in amplitude or waveform, implying that the type II fiber's length constant exceeded the length of the synaptic input zone. Together these data suggest that type II fibers could communicate centrally by maximal activation of their entire pool of presynaptic OHCs.
    Journal of Neuroscience 07/2012; 32(28):9528-36. · 6.91 Impact Factor
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    ABSTRACT: Efferent innervation of the cochlea undergoes extensive modification early in development, but it is unclear if efferent synapses are modified by age, hearing loss, or both. Structural alterations in the cochlea affecting information transfer from the auditory periphery to the brain may contribute to age-related hearing deficits. We investigated changes to efferent innervation in the vicinity of inner hair cells (IHCs) in young and old C57BL/6 mice using transmission electron microscopy to reveal increased efferent innervation of IHCs in older animals. Efferent contacts on IHCs contained focal presynaptic accumulations of small vesicles. Synaptic vesicle size and shape were heterogeneous. Postsynaptic cisterns were occasionally observed. Increased IHC efferent innervation was associated with a smaller number of afferent synapses per IHC, increased outer hair cell loss, and elevated auditory brainstem response thresholds. Efferent axons also formed synapses on afferent dendrites but with a reduced prevalence in older animals. Age-related reduction of afferent activity may engage signaling pathways that support the return to an immature state of efferent innervation of the cochlea.
    Neurobiology of aging 03/2012; 33(12):2892-902. · 5.94 Impact Factor
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    ABSTRACT: The α9 and α10 cholinergic nicotinic receptor subunits assemble to form the receptor that mediates efferent inhibition of hair cell function within the auditory sensory organ, a mechanism thought to modulate the dynamic range of hearing. In contrast to all nicotinic receptors, which serve excitatory neurotransmission, the activation of α9α10 produces hyperpolarization of hair cells. An evolutionary analysis has shown that the α10 subunit exhibits signatures of positive selection only along the mammalian lineage, strongly suggesting the acquisition of a unique function. To establish whether mammalian α9α10 receptors have acquired distinct functional properties as a consequence of this evolutionary pressure, we compared the properties of rat and chicken recombinant and native α9α10 receptors. Our main finding in the present work is that, in contrast to the high (pCa(2+)/pMonovalents ∼10) Ca(2+) permeability reported for rat α9α10 receptors, recombinant and native chicken α9α10 receptors have a much lower permeability (∼2) to this cation, comparable to that of neuronal α4β2 receptors. Moreover, we show that, in contrast to α10, α7 as well as α4 and β2 nicotinic subunits are under purifying selection in vertebrates, consistent with the conserved Ca(2+) permeability reported across species. These results have important consequences for the activation of signaling cascades that lead to hyperpolarization of hair cells after α9α10 gating at the cholinergic-hair cell synapse. In addition, they suggest that high Ca(2+) permeability of the α9α10 cholinergic nicotinic receptor might have evolved together with other features that have given the mammalian ear an expanded high-frequency sensitivity.
    Proceedings of the National Academy of Sciences 02/2012; 109(11):4308-13. · 9.74 Impact Factor
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    ABSTRACT: In the developing mammalian cochlea, the sensory hair cells receive efferent innervation originating in the superior olivary complex. This input is mediated by α9/α10 nicotinic acetylcholine receptors (nAChRs) and is inhibitory due to the subsequent activation of calcium-dependent SK2 potassium channels. We examined the acquisition of this cholinergic efferent input using whole-cell voltage-clamp recordings from inner hair cells (IHCs) in acutely excised apical turns of the rat cochlea from embryonic day 21 to postnatal day 8 (P8). Responses to 1 mm acetylcholine (ACh) were detected from P0 on in almost every IHC. The ACh-activated current amplitude increased with age and demonstrated the same pharmacology as α9-containing nAChRs. Interestingly, at P0, the ACh response was not coupled to SK2 channels, so that the initial cholinergic response was excitatory and could trigger action potentials in IHCs. Coupling to SK current was detected earliest at P1 in a subset of IHCs and by P3 in every IHC studied. Clustered nAChRs and SK2 channels were found on IHCs from P1 on using Alexa Fluor 488 conjugated α-bungarotoxin and SK2 immunohistochemistry. The number of nAChRs clusters increased with age to 16 per IHC at P8. Cholinergic efferent synaptic currents first appeared in a subset of IHCs at P1 and by P3 in every IHC studied, contemporaneously with ACh-evoked SK currents, suggesting that SK2 channels may be necessary at onset of synaptic function. An analogous pattern of development was observed for the efferent synapses that form later (P6-P8) on outer hair cells in the basal cochlea.
    Journal of Neuroscience 10/2011; 31(42):15092-101. · 6.91 Impact Factor
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    ABSTRACT: In the mammalian inner ear, the gain control of auditory inputs is exerted by medial olivocochlear (MOC) neurons that innervate cochlear outer hair cells (OHCs). OHCs mechanically amplify the incoming sound waves by virtue of their electromotile properties while the MOC system reduces the gain of auditory inputs by inhibiting OHC function. How this process is orchestrated at the synaptic level remains unknown. In the present study, MOC firing was evoked by electrical stimulation in an isolated mouse cochlear preparation, while OHCs postsynaptic responses were monitored by whole-cell recordings. These recordings confirmed that electrically evoked IPSCs (eIPSCs) are mediated solely by α9α10 nAChRs functionally coupled to calcium-activated SK2 channels. Synaptic release occurred with low probability when MOC-OHC synapses were stimulated at 1 Hz. However, as the stimulation frequency was raised, the reliability of release increased due to presynaptic facilitation. In addition, the relatively slow decay of eIPSCs gave rise to temporal summation at stimulation frequencies >10 Hz. The combined effect of facilitation and summation resulted in a frequency-dependent increase in the average amplitude of inhibitory currents in OHCs. Thus, we have demonstrated that short-term plasticity is responsible for shaping MOC inhibition and, therefore, encodes the transfer function from efferent firing frequency to the gain of the cochlear amplifier.
    Journal of Neuroscience 10/2011; 31(41):14763-74. · 6.91 Impact Factor
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    Eric Wersinger, Paul Albert Fuchs
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    ABSTRACT: Outer hair cells (OHCs) amplify the sound-evoked motion of the basilar membrane to enhance acoustic sensitivity and frequency selectivity. Medial olivocochlear (MOC) efferents inhibit OHCs to reduce the sound-evoked response of cochlear afferent neurons. OHC inhibition occurs through the activation of postsynaptic α9α10 nicotinic receptors tightly coupled to calcium-dependent SK2 channels that hyperpolarize the hair cell. MOC neurons are cholinergic but a number of other neurotransmitters and neuromodulators have been proposed to participate in efferent transmission, with emerging evidence for both pre- and postsynaptic effects. Cochlear inhibition in vivo is maximized by repetitive activation of the efferents, reflecting facilitation and summation of transmitter release onto outer hair cells. This review summarizes recent studies on cellular and molecular mechanisms of cholinergic inhibition and the regulation of those molecular components, in particular the involvement of intracellular calcium. Facilitation at the efferent synapse is compared in a variety of animals, as well as other possible mechanisms of modulation of ACh release. These results suggest that short-term plasticity contributes to effective cholinergic inhibition of hair cells.
    Hearing research 12/2010; 279(1-2):1-12. · 2.18 Impact Factor
  • Eleonora Katz, Ana Belén Elgoyhen, Paul Albert Fuchs
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    ABSTRACT: In the inner ear, the activity of hair cells that transform sound into electrical signals is modulated by a descending efferent innervation from the brain. A major component of this feedback involves cholinergic inhibition of hair cells via an unusual ionic mechanism. It activates rapidly (on the order of milliseconds), but instead of being mediated by a hyperpolarizing conductance through γ-aminobutyric acid (GABA) and/or glycine receptors, it is served by nicotinic cholinergic receptors (nAChR), which usually mediate excitatory postsynaptic responses. How is fast inhibition accomplished if the activation of a cationic channel (the nAChR) at the resting membrane potential should depolarize the hair cell?
    11/2010: pages 103-133;
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    Gary Matthews, Paul Fuchs
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    ABSTRACT: Sensory synapses of the visual and auditory systems must faithfully encode a wide dynamic range of graded signals, and must be capable of sustained transmitter release over long periods of time. Functionally and morphologically, these sensory synapses are unique: their active zones are specialized in several ways for sustained, rapid vesicle exocytosis, but their most striking feature is an organelle called the synaptic ribbon, which is a proteinaceous structure that extends into the cytoplasm at the active zone and tethers a large pool of releasable vesicles. But precisely how does the ribbon function to support tonic release at these synapses? Recent genetic and biophysical advances have begun to open the 'black box' of the synaptic ribbon with some surprising findings and promise to resolve its function in vision and hearing.
    Nature Reviews Neuroscience 11/2010; 11(12):812-22. · 31.38 Impact Factor
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    ABSTRACT: Outer hair cells are the specialized sensory cells that empower the mammalian hearing organ, the cochlea, with its remarkable sensitivity and frequency selectivity. Sound-evoked receptor potentials in outer hair cells are shaped by both voltage-gated K(+) channels that control the membrane potential and also ligand-gated K(+) channels involved in the cholinergic efferent modulation of the membrane potential. The objectives of this study were to investigate the tonotopic contribution of BK channels to voltage- and ligand-gated currents in mature outer hair cells from the rat cochlea. Findings In this work we used patch clamp electrophysiology and immunofluorescence in tonotopically defined segments of the rat cochlea to determine the contribution of BK channels to voltage- and ligand-gated currents in outer hair cells. Although voltage and ligand-gated currents have been investigated previously in hair cells from the rat cochlea, little is known about their tonotopic distribution or potential contribution to efferent inhibition. We found that apical (low frequency) outer hair cells had no BK channel immunoreactivity and little or no BK current. In marked contrast, basal (high frequency) outer hair cells had abundant BK channel immunoreactivity and BK currents contributed significantly to both voltage-gated and ACh-evoked K(+) currents. Our findings suggest that basal (high frequency) outer hair cells may employ an alternative mechanism of efferent inhibition mediated by BK channels instead of SK2 channels. Thus, efferent synapses may use different mechanisms of action both developmentally and tonotopically to support high frequency audition. High frequency audition has required various functional specializations of the mammalian cochlea, and as shown in our work, may include the utilization of BK channels at efferent synapses. This mechanism of efferent inhibition may be related to the unique acetylcholine receptors that have evolved in mammalian hair cells compared to those of other vertebrates.
    PLoS ONE 01/2010; 5(11):e13836. · 3.73 Impact Factor
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    ABSTRACT: The mammalian cochlea is innervated by two classes of sensory neurons. Type I neurons make up 90-95% of the cochlear nerve and contact single inner hair cells to provide acoustic analysis as we know it. In contrast, the far less numerous type II neurons arborize extensively among outer hair cells (OHCs) and supporting cells. Their scarcity and smaller calibre axons have made them the subject of much speculation, but little experimental progress for the past 50 years. Here we record from type II fibres near their terminal arbors under OHCs to show that they receive excitatory glutamatergic synaptic input. The type II peripheral arbor conducts action potentials, but the small and infrequent glutamatergic excitation indicates a requirement for strong acoustic stimulation. Furthermore, we show that type II neurons are excited by ATP. Exogenous ATP depolarized type II neurons, both directly and by evoking glutamatergic synaptic input. These results prove that type II neurons function as cochlear afferents, and can be modulated by ATP. The lesser magnitude of synaptic drive dictates a fundamentally different role in auditory signalling from that of type I afferents.
    Nature 10/2009; 461(7267):1126-9. · 38.60 Impact Factor
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    ABSTRACT: Efferent inhibition of cochlear hair cells is mediated by alpha9alpha10 nicotinic cholinergic receptors (nAChRs) functionally coupled to calcium-activated, small conductance (SK2) potassium channels. Before the onset of hearing, efferent fibers transiently make functional cholinergic synapses with inner hair cells (IHCs). The retraction of these fibers after the onset of hearing correlates with the cessation of transcription of the Chrna10 (but not the Chrna9) gene in IHCs. To further analyze this developmental change, we generated a transgenic mice whose IHCs constitutively express alpha10 into adulthood by expressing the alpha10 cDNA under the control of the Pou4f3 gene promoter. In situ hybridization showed that the alpha10 mRNA is expressed in IHCs of 8-week-old transgenic mice, but not in wild-type mice. Moreover, this mRNA is translated into a functional protein, since IHCs from P8-P10 alpha10 transgenic mice backcrossed to a Chrna10(-/-) background (whose IHCs have no cholinergic function) displayed normal synaptic and acetylcholine (ACh)-evoked currents in patch-clamp recordings. Thus, the alpha10 transgene restored nAChR function. However, in the alpha10 transgenic mice, no synaptic or ACh-evoked currents were observed in P16-18 IHCs, indicating developmental down-regulation of functional nAChRs after the onset of hearing, as normally observed in wild-type mice. The lack of functional ACh currents correlated with the lack of SK2 currents. These results indicate that multiple features of the efferent postsynaptic complex to IHCs, in addition to the nAChR subunits, are down-regulated in synchrony after the onset of hearing, leading to lack of responses to ACh.
    Journal of the Association for Research in Otolaryngology 06/2009; 10(3):397-406. · 2.95 Impact Factor
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    ABSTRACT: Mechanosensory hair cells of the organ of Corti transmit information regarding sound to the central nervous system by way of peripheral afferent neurons. In return, the central nervous system provides feedback and modulates the afferent stream of information through efferent neurons. The medial olivocochlear efferent system makes direct synaptic contacts with outer hair cells and inhibits amplification brought about by the active mechanical process inherent to these cells. This feedback system offers the potential to improve the detection of signals in background noise, to selectively attend to particular signals, and to protect the periphery from damage caused by overly loud sounds. Acetylcholine released at the synapse between efferent terminals and outer hair cells activates a peculiar nicotinic cholinergic receptor subtype, the alpha9alpha10 receptor. At present no pharmacotherapeutic approaches have been designed that target this cholinergic receptor to treat pathologies of the auditory system. The potential use of alpha9alpha10 selective drugs in conditions such as noise-induced hearing loss, tinnitus and auditory processing disorders is discussed.
    Biochemical pharmacology 06/2009; 78(7):712-9. · 4.25 Impact Factor
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    ABSTRACT: The transduction of sound in the auditory periphery, the cochlea, is inhibited by efferent cholinergic neurons projecting from the brainstem and synapsing directly on mechanosensory hair cells. One fundamental question in auditory neuroscience is what role(s) this feedback plays in our ability to hear. In the present study, we have engineered a genetically modified mouse model in which the magnitude and duration of efferent cholinergic effects are increased, and we assess the consequences of this manipulation on cochlear function. We generated the Chrna9L9'T line of knockin mice with a threonine for leucine change (L9'T) at position 9' of the second transmembrane domain of the alpha9 nicotinic cholinergic subunit, rendering alpha9-containing receptors that were hypersensitive to acetylcholine and had slower desensitization kinetics. The Chrna9L9'T allele produced a 3-fold prolongation of efferent synaptic currents in vitro. In vivo, Chrna9L9'T mice had baseline elevation of cochlear thresholds and efferent-mediated inhibition of cochlear responses was dramatically enhanced and lengthened: both effects were reversed by strychnine blockade of the alpha9alpha10 hair cell nicotinic receptor. Importantly, relative to their wild-type littermates, Chrna9(L9'T/L9'T) mice showed less permanent hearing loss following exposure to intense noise. Thus, a point mutation designed to alter alpha9alpha10 receptor gating has provided an animal model in which not only is efferent inhibition more powerful, but also one in which sound-induced hearing loss can be restrained, indicating the ability of efferent feedback to ameliorate sound trauma.
    PLoS Biology 02/2009; 7(1):e18. · 12.69 Impact Factor
  • Biochemical Pharmacology - BIOCHEM PHARMACOL. 01/2009; 78(7):899-899.
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    ABSTRACT: This review will cover advances in the study of hair cell afferent synaptic function occurring between 2005 and 2008. During this time, capacitance measurements of vesicular fusion have continued to be refined, optical methods have added insights regarding vesicle trafficking, and paired intracellular recordings have established the transfer function of the afferent synapse at high resolution. Further, genes have been identified with forms of deafness known as auditory neuropathy, and their role in afferent signaling explored in mouse models. With these advances, our view of the hair cell afferent synapse has continued to be refined, and surprising properties have been revealed that emphasize the unique role of this structure in neural function.
    Current Opinion in Neurobiology 11/2008; 18(4):389-95. · 7.34 Impact Factor
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    Jee-Hyun Kong, John P Adelman, Paul A Fuchs
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    ABSTRACT: Efferent inhibition of cochlear hair cells is mediated by 'nicotinic' cholinergic receptors functionally coupled to calcium-activated, small conductance (SK2) potassium channels. We recorded from cochlear hair cells in SK2 knockout mice to evaluate further the role of this channel in efferent function. Since cholinergic inhibitory synapses can be found on inner or outer hair cells, depending on developmental age, both cell types were studied. To determine if SK channel activity was indeed eliminated, seconds-long voltage-gated calcium influx was used to activate slowly rising and falling calcium-dependent potassium currents. These were identified as SK currents by their time course, calcium dependence and sensitivity to block by apamin in wild-type IHCs. IHCs from knockout mice had no SK current by these same criteria. Thus, the SK2 gene is solely responsible for encoding the SK channels of inner hair cells. Other aspects of hair cell excitability remained relatively unaffected. Unexpectedly, cholinergic synaptic currents were entirely absent from both inner and outer SK2-knockout hair cells. Further, direct application of ACh caused no change in membrane current, implying absent or otherwise dysfunctional ACh receptors. Immunohistology of whole-mounts using the antibody to the synaptic vesicle protein 2 (SV2) revealed a pronounced reduction of efferent innervation to outer hair cells (OHCs) in the knockout cochleas. Quantitative RT-PCR analysis, however, showed no change in the mRNA levels of alpha9 and alpha10 nicotinic ACh receptor (nAChR) genes. Thus, some aspect of translation or subsequent protein processing leads to non-functional or absent ACh receptors. These results indicate that SK2 channels are required both for expression of functional nAChRs, and for establishment and/or maintenance of efferent terminals in the cochlea.
    The Journal of Physiology 10/2008; 586(Pt 22):5471-85. · 4.38 Impact Factor

Publication Stats

2k Citations
386.90 Total Impact Points

Institutions

  • 2008–2012
    • Johns Hopkins Medicine
      • Department of Otolaryngology - Head and Neck Surgery
      Baltimore, MD, United States
  • 2004–2011
    • National Scientific and Technical Research Council
      • INGEBI - Instituto de Investigaciones en Ingeniería Genética y Biología Molecular
      Mendoza, Provincia de Mendoza, Argentina
  • 1996–2011
    • Johns Hopkins University
      • • Department of Otolaryngology - Head and Neck Surgery
      • • Department of Neuroscience
      Baltimore, MD, United States
    • University of Colorado Hospital
      • Department of Physiology
      Denver, Colorado, United States
  • 2010
    • Stony Brook University
      • Department of Neurobiology and Behavior
      Stony Brook, NY, United States
  • 2007
    • Hanyang University
      Sŏul, Seoul, South Korea
  • 2003
    • University of Maryland, Baltimore
      • Department of Otorhinolaryngology - Head and Neck Surgery
      Baltimore, Maryland, United States
  • 1999
    • University of Wisconsin–Madison
      Madison, Wisconsin, United States