Hair cell afferent synapses
Introduction
Hair cells are the mechanosensors of the inner ear, converting the mechanical energy of sound or head movements into receptor potentials for transmission to afferent neurons whose action potentials carry that information to the central nervous system. Neurotransmission occurs across specialized synaptic structures, named synaptic ribbons after their resemblance to those found in retinal photoreceptors and bipolar cells [1, 2, 3]. Like retinal synapses, hair cell ribbon synapses are said to be ‘tonic’ in the sense that they release neurotransmitter continuously in the absence of frank stimulation, and do so without generating action potentials presynaptically. Synaptic transmission is driven by graded changes in hair cell membrane potential, but expressed in the postsynaptic afferent neuron as a rate code of action potential frequency. The coding of sound and head motion by single afferent fibers has been studied extensively [4] and provides a rich context in which to probe hair cell synaptic function. In this review we will focus on the inner hair cell to Type I afferent synapse of the mammalian cochlea, with some comparative examples. Less is known about transmission from outer hair cells to Type II afferents. However recent studies have shown that outer hair cells possess the functional attributes of transmitter release: voltage-gated calcium channels [5•, 6] and voltage-dependent capacitance changes [7•]. Future effort here promises to provide intriguing insights since a majority of these contacts occur without ribbons in the outer hair cells [8], and glutamate receptors, if present, appear to be different from those at inner hair cell contacts [9].
Section snippets
Voltage-gated calcium channels
The hair cell's receptor potentials drive transmitter release through the activation of voltage-gated calcium channels. In cochlear hair cells these are encoded by the CaV1.3 (α1D) gene [10], a member of the dihydropyridine-sensitive, L-type channel class related to those of cardiac and skeletal muscle. In keeping with the frequency-coding demands on hair cells, hair cell voltage-gated calcium currents are very rapidly gating (time constant of activation on the order of 300 μs at room
Calcium buffering
Hair cells are subject to ongoing calcium influx at both their ciliary and synaptic poles. Because overaccumulation can be toxic, hair cells must spend energy to buffer, sequester, or extrude calcium. More particularly, afferent synaptic function requires calcium transients that rise and fall rapidly in order to encode the temporal content of sounds, including phase-locking to several kHz. Estimates of diffusible calcium buffers in hair cells have been based on a method of comparison whereby a
Molecular components of transmitter release
Hair cells express some, but not all components of the so-called ‘SNARE’ complex that mediates calcium-dependent vesicular fusion in presynaptic terminals. In particular, hair cells do not have synaptotagmin I or II [21], perhaps substituted with the novel ‘deafness gene’ product, otoferlin. Mutations in human otoferlin result in nonsyndromic auditory neuropathy (DFNB9) [22], deafness resulting from deficits downstream of cochlear mechano-transduction. Like synaptotagmin, otoferlin interacts
The synaptic transfer function
In addition to molecular identification of constituents of the ribbon synapse, there has been considerable insight gained into its physiology, especially the quantitative relationship between the hair cell's membrane potential and transmitter release onto the postsynaptic afferent. The fundamental calcium sensitivity of vesicular fusion has been measured as a change in membrane capacitance produced in two ways: by variation of calcium influx as a function of driving force, rather than channel
Vesicle recycling
Measurements of capacitance in hair cells can reveal both the addition, and subtraction of vesicular membrane as exocytosis and endocytosis proceed [40, 41]. After sustained depolarization of frog saccular hair cells, synaptic vesicles decline in number, and large endocytic cisterns arise, which might be a source of synaptic vesicles [42]. Whatever the mechanism, such slow endocytosis (τ 7–14 s) is certainly inadequate to support the hair cell's rapid, continuous vesicular release, suggesting
Multivesicular release
A surprising aspect of ribbon transmission is that multiple vesicles can be released at once, even without a change in membrane potential. Initial evidence for multivesicular release was found at the inner hair cell afferent synapse in the postnatal rat cochlea [45]. In this preparation the auditory nerve fiber receives input from just one afferent terminal, usually contacting a single inner hair cell ribbon synapse. Patch clamp recordings from the afferent terminal showed
Hair cell vesicular glutamate transporters
Early in the process of preparing glutamatergic synaptic vesicles for release, vesicular glutamate transporters (VGLUTs) fill vesicles with neurotransmitter. There are three VGLUT isoforms in the mammalian CNS, VGLUT1–3 [55]. Three recent studies using forward and reverse genetic approaches concluded that VGLUT3 is the VGLUT required for hair cell afferent transmission. Mice lacking VGLUT3 were profoundly deaf [56••, 57••], and a mutagenesis screen turned up a zebrafish larval mutant, asteroid
Postsynaptic glutamate receptors
It is well established that AMPA receptors mediate fast synaptic transmission at the hair cell afferent synapse [36••, 45, 60]. Chen et al. [61••] have provided evidence that synaptic strength might be modulated by AMPA receptor cycling at the afferent fiber postsynaptic density. They showed that acoustic trauma in mice caused a reduction of surface AMPA (GluR2) receptors in auditory nerve fibers. The recovery of acoustic thresholds and surface AMPA receptors followed a similar time course. The
Conclusions
Afferent (ribbon) synapses of hair cells have to meet a number of functional challenges, including sustained (tonic) activity and rapid temporal coding. To do so the hair cell's calcium channels do not fully inactivate, thus supporting tonic release, and potent buffering mechanisms rapidly modulate free calcium. Through as yet unknown mechanisms, a virtually unlimited supply of vesicles is marshalled for release at the ribbon synapse, presumably from a large, freely mobile cytoplasmic pool.
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
Work in the authors’ laboratories was supported by the National Institute on Deafness and Other Communication Disorders grants DC006476 to EG, DC000276 to PAF, and P30 DC005211.
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2017, Hearing ResearchCitation Excerpt :Based on the expression of ion channels permeable to calcium in SGNs, both L-type and T-type calcium channels could contribute to this excess calcium after noise trauma, and our recent studies have implicated T-type calcium channels as playing an important role in NIHL (Bao et al., 2013; Kopecky et al., 2014). Besides excessive calcium influx in postsynaptic terminals, another consequence of noise exposure is an increase of calcium in hair cells (Glowatzki et al., 2008), which could lead to a further calcium release from intracellular storages. The excess calcium increase could lead to not only excessive release of glutamate to damage postsynaptic structures, but also activations of down-stream calcium dependent pathways such as calcium/calmodulin-dependent protein phosphatase, which in turn activates mitochondria-mediated cell death pathways (Oishi and Schacht, 2011).
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2015, Hearing ResearchCitation Excerpt :This precision is required in order to, for example, encode ITD in the microsecond range for locating a sound source (Moser et al., 2006). The sound pressure level is transduced into the graded receptor potentials of IHCs that then drive firing of postsynaptic SGNs at a rate reflecting the stimulus intensity (rate code) (Nouvian et al., 2006; Glowatzki et al., 2008; Peterson et al., 2014). One anatomical feature of IHCs strikingly contrasts the arrangement of calyceal synapses with hundreds of active zones originating from one terminal converging onto a principal cell (Figs. 1C and 2B).
No longer falling on deaf ears: Mechanisms of degeneration and regeneration of cochlear ribbon synapses
2015, Hearing ResearchCitation Excerpt :It has been proposed that this acquired cochlear synaptopathy is primarily caused by glutamate excitotoxicity (Chen et al., 2004; Puel et al., 1998, 1994; Ruel et al., 2007) and underlies loss of hearing acuity in noisy environments (Furman et al., 2013; Kujawa and Liberman, 2009; Sergeyenko et al., 2013). Several recent articles have reviewed in depth aspects of cochlear ribbon synapse biology, including their formation, structure and function (Glowatzki et al., 2008; Matthews and Fuchs, 2010; Moser et al., 2006; Nouvian et al., 2006; Safieddine et al., 2012; Sterling and Matthews, 2005; Yu and Goodrich, 2014). Here we will discuss current knowledge on how ribbon synapses are damaged by injury and normal aging, and the consequence of this damage to auditory function.