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Voltage-Gated Calcium Channels at the Hair Cell Ribbon Synapse Thomas M Coate and Conant BMC Biology (2018) 16:105 https://doi.org/10.1186/s12915-018-0575-7 COMMENTARY Open Access Brevican “nets” voltage-gated calcium channels at the hair cell ribbon synapse Thomas M. Coate1* and Katherine Conant2* Abstract During hearing in mammals, “sensorineural” inner hair cells convert sound wave-generated mechanical input into electrical activity, resulting in glutamate release onto type I spiral ganglion neurons (SGNs) at specialized synapses known as “ribbon synapses”. New findings published here in BMC Biology by Sonntag and colleagues indicate a role for the proteoglycan Brevican in forming perineurounal net (PNN) baskets at these synapses and controlling the spatial distribution of presynaptic voltage-gated calcium channels that regulate glutamate release. These findings may provide insight into the mechanism by which individual ribbon synapses within a single hair cell can function in an independent manner to facilitate hearing within a broad dynamic range. Commentary the hair cell ribbon synapse where they may prevent glu- The base of an adult mouse inner hair cell (IHC) con- tamate spillover to neighboring synapses. These proteins tains around 20 presynaptic ribbon bodies, each of have not been well characterized in the peripheral audi- which is dominated by an electron-dense spherical struc- tory system, and the data in this report suggest they may ture covered in glutamate-containing synaptic vesicles be important regulators of auditory afferent transmission. (Fig. 1). Along the landscape of the inner hair cell, the PNNs are a specialized form of dense extracellular ribbon bodies and postsynaptic densities that juxtapose matrix (ECM) that surround select neuronal subpopula- them show remarkable heterogeneity in size, and differ- tions within the central nervous system (CNS). These ences in size are known to correlate with their spatially lattice-like structures predominantly associate with neur- distinct positions within the inner hair cell [1]. Type I onal types that are fast spiking and metabolically active, SGNs, the primary afferents of the auditory system, are and thus they have been well studied for their ability to also heterogeneous and can be broken into three classes protect enveloped cells from oxidant stress [4]. Recent based on a variety of features, including physiological work also suggests that, since PNNs closely border syn- parameters, morphology, and molecular profiles [2]. The aptic contacts, their presence can facilitate the reliability ribbon presynaptic region contains a plethora of scaf- and temporal precision of fast synaptic transmission. Con- folding and regulatory factors necessary for glutamate sistent with this, PNN disruption has been shown to en- release, including Bassoon, Ribeye, Vglut3, Cav1.3, and hance the lateral mobility of GluAs, which may reduce many others. The molecular composition of the postsyn- post-synaptic receptor engagement [5]. It has also been aptic density includes scaffolding proteins like Shank1 suggested PNN disruption can enhance synaptically re- and PSD95, and although nearly all forms of glutamate leased glutamate dispersion Indeed, in mice deficient for receptors are expressed by the SGNs, AMPA-type glu- the PNN component Brevican, excitatory input from pyr- tamate receptors are almost entirely responsible for their amidal cells to PNN-surrounded parvalbumin-expressing excitability. The beautiful immunostaining studies shown fast spiking interneurons is reduced [6]. by Sonntag et al. [3] show that PNN proteins such as Sonntag et al. now report the presence of basket-like Brevican, Aggrecan, and HAPLN1 are present around ECM structures that contain classic PNN components, including Brevican external to the CNS and specifically * Correspondence: [email protected]; [email protected] at the synaptic poles of inner hair cells (IHCs). Given 1Department of Biology, Georgetown University, 37th and O St. NW, that IHC signaling is high frequency and continuous [7], Washington, DC 20007, USA this localization lends additional support to the idea that 2Department of Neuroscience, Georgetown University Medical Center, 3970 Reservoir Road, Washington, DC 20007, USA PNNs support the fidelity of synaptic transmission at © Conant et al. 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Coate and Conant BMC Biology (2018) 16:105 Page 2 of 3 Fig. 1 Overview of the IHC-SGN synapse. Shown is a cochlear inner hair cell with SGN contacts. In the expanded view of a wild-type (WT) contact, an individual release site of a ribbon synapse is shown with alignment of presynaptic Cav1.3 channels and the post-synaptic density of an SGN contact. This arrangement likely facilitates spatially precise neurotransmitter release. With injury or other conditions that may increase expression of PNN- targeting extracellular proteases, Cav1.3 channels could be misaligned and spatially precise transmitter release impaired in a manner similar to that shown in the expanded view of a bcan−/− contact. A lateral olivocochlear (LOC) efferent contact to an SGN dendrite is also shown sites that require faithful transmission and high temporal et al. propose that unique Brevican baskets may separate precision. Cav1.3 proteins tightly cluster around individual these individual sites and potentially prevent glutamate ribbon synapses and are necessary for proper glutamate spillover to preserve appropriate transmission within a release at those discrete sites [8]. Sonntag et al. show that, large dynamic range. in Brevican-deficient mice, the colocalization of presynap- The finding that PNNs may affect transmission at the tic Cav1.3 and post-synaptic density-95 labeling is dis- IHC-SGN synapse has several implications. For example, rupted, and presumably this dislocation leads to defects in in ototoxic noise exposure an increase in cochlear react- afferent firing. If this were the case, it would be reasonable ive oxygen and nitrogen species is observed. These spe- to conclude that PNN integrity is needed to support the cies may in turn upregulate the expression of spatial fidelity of glutamatergic neurotransmission. PNN-degrading proteases to influence synaptic trans- We note here that cochlear efferents (arising from the mission and/or cell viability. lateral superior olivary complex) also form synapses on At least three important questions in the area of PNNs the endings of the type I SGNs, adjacent to the afferent and auditory afferent transduction should now be ad- synapses. The lateral efferents are known to release sev- dressed. First, how and when do PNNs assemble in the eral neurotransmitters, including acetylcholine and context of ribbon synapse formation in the cochlea? In dopamine, that may be important protectors against mouse, initial connectivity between SGNs and hair cells auditory neuropathy [9] and are in very close proximity occurs starting around E14.5, and the maturation of the to the apparent location of the PNN proteins. While ribbon synapses occurs from around P0 through P10 PNNs have been best studied for their effects on gluta- (when hearing commences). During this latter phase, the matergic transmission [5], it is possible that the PNNs SGNs engage in an elaborate series of events including introduced in this report also interact with and influence branching refinement, spontaneous firing, myelination the lateral efferent synapses in some manner. by Schwann cells, synaptic pruning, and innervation by The IHC ribbon synapse is relatively unique. In par- efferents. After hearing onset, afferent firing characteris- ticular, neurotransmitter release sites exist and are com- tics and the ribbon synaptic structures go through a pro- partmentalized within a single cell such that each tracted phase of maturation through around P30 [1, 10]. afferent is activated by only the presynaptic ribbon adja- In the future, it will be important to determine the time- cent to it. This differs from other types of hair cells, like line of PNN formation in the context of auditory devel- type I hair cells in the vestibular system, which are in- opment and the extent to which any of these events nervated by an afferent calyx that receives glutamate re- affect PNNs or vice versa. This could enhance our un- leased from multiple ribbons. Furthermore, the firing derstanding of the cellular and molecular role(s) of properties of each afferent are highly variable, and pairs PNNs in ribbon synapse formation and may help deter- of afferents contacting the same inner hair cell do not mine if PNNs could be useful therapeutic targets in ef- show any correlations in activity [10]. Thus, each ribbon forts to re-wire the cochlea following damage. Second, it body–afferent pairing can be assumed to act as an indi- will be of interest to evaluate how loss of the perineuro- vidual channel within a single inner hair cell. Sonntag nal baskets affects afferent firing. In this paper, the Coate and Conant BMC Biology (2018) 16:105 Page 3 of 3 authors showed convincingly
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