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Auditory System: Giant Synaptic Terminals, Endbulbs, and Calyces 759 Author's personal copy Auditory System: Giant Synaptic Terminals, Endbulbs, and Calyces 759 Auditory System: Giant Synaptic Terminals, Endbulbs, and Calyces D K Ryugo , Johns Hopkins University School of 1893. They were characterized in kittens as axoso- Medicine, Baltimore, MD, USA matic, spoon-shaped endings with many filopodia G A Spirou , West Virginia University, Morgantown, that marked the end of the anterior branch of the WV, USA fiber (Figure 1, left). When endings of the anterior ã 2009 Elsevier Ltd. All rights reserved. branch were labeled in the same location of the adult cat, however, they appeared vastly different (Figure 1, right). The question was whether the differences were due to staining techniques or age of the animal stud- Introduction ied. These endings were analyzed in an age-graded The inescapable relationship between form and func- series of cats using the Golgi stain and horseradish tion in biological systems has focused attention on the peroxidase (HRP), demonstrating that the structural giant synaptic endings in the central auditory system. differences were due to the age of the animal examined (Figure 2). Auditory nerve fibers from every vertebrate Two of these giant endings are the subject of this article: endbulbs of Held that arise from myelinated examined have exhibited large axosomatic endbulbs auditory nerve fibers and calyces of Held that arise of Held. These include the red-eared turtle, alligator lizard, chickens, owls, guinea pigs, rats, cats, monkeys, from globular bushy cells of the cochlear nucleus. These endings form hundreds of synapses with their and humans. Endbulbs are found in the anteroventral targets and are implicated in fail-safe synaptic trans- cochlear nucleus and make synaptic contact with neu- mission that faithfully couples neural activity to envi- rons known as spherical bushy cells. ronmental auditory events. The importance of this The phylogenetically conserved ending implies linkage is the preservation of neural timing that codes functional significance for the processing of acoustic for all aspects of sound. Sounds only have significance information. The size of the ending suggests powerful synaptic drive on the postsynaptic cell. The faithful to us when they occur over time. This preservation of timing within auditory signals enables the translation transmission of presynaptic activity to the postsynap- of prosodic utterances into perceptible speech and the tic cell ensures that neural activity in the brain is yoked in time to acoustic events. The precision of processing of two cues used to localize sounds in space, interaural time differences (ITDs) and inter- the timing forms the substrate for sound localization aural level (intensity) differences (ILDs). as well as for translating sequences of sounds into The ITD and the ILD pathways contain some of the perceptible speech. largest, fastest, and most powerful synaptic endings in the central nervous system. The ITD pathway is Synapses: Presynaptic Endings initiated by the myelinated auditory nerve fibers that give rise to large and highly branched axosomatic The reliability of transmission at this synapse was inferred from the observation that a small positive endings called the endbulbs of Held. One or two of these endbulbs converge onto the cell body of a spher- potential, called the prepotential, occurred 0.5 ms ical bushy cell in the anteroventral cochlear nucleus prior to the action potential. The prepotential was interpreted to represent the depolarization of the end- (AVCN) that, in turn, transmits high-fidelity tempo- ral information bilaterally to structures in the supe- bulb, and the coupling between prepotential and spike rior olivary complex. The ILD pathway is initiated by resulted in the notion of a fail-safe synapse that may nonetheless be modulated by inhibition. This ending myelinated auditory nerve fibers that give rise to many smaller endbulbs that converge onto globular has between 400 and 1500 release sites as calculated bushy cells in the AVCN. Globular bushy cells project through serial section electron microscopy. The re- to the contralateral medial nucleus of the trapezoid lease sites of endbulbs have the morphology typical of normal synapses in the central nervous system body (MNTB) and form a giant axosomatic synaptic ending called the calyx of Held. These two giant end- (Figure 3). They are characterized by the presynaptic ings represent the key components for preserving assemblage of clear, round synaptic vesicles, approxi- mately 50–55 nm in diameter, that accumulate across timing in the auditory system. from convex, dome-shaped postsynaptic densities Endbulbs of Held: Morphology (PSDs) of the postsynaptic membrane. The postsynaptic density is visible as a small (on the m Large endings of auditory nerve fibers were originally order of 0.5 m in diameter or less) aggregation of described in Golgi-stained material by Hans Held in electron-dense material on the cytoplasmic side of the Encyclopedia of Neuroscience (2009), vol. 1, pp. 759-770 Author's personal copy 760 Auditory System: Giant Synaptic Terminals, Endbulbs, and Calyces Figure 1 Left panel: Golgi-stained endbulbs of Held from neonatal kittens. They appear as spoon-shaped swellings with filopodia, identical to the original description by Hans Held in 1893. Right panel: HRP-labeled endbulb from an adult cat. The contrast in morphology of neonatal and adult cat endbulbs raised the question as to whether the differences were due to staining methods or age of the animals. target membrane. The density is composed of neuro- currents in cochlear nucleus slice recordings are bloc- transmitter receptors, ion channels, signal transduc- ked by glutamate receptor antagonists. tion proteins, cytoskeletal proteins that anchor receptors to the postsynaptic site, and adhesion mol- Synapses: Postsynaptic Targets ecules for proper alignment of pre- and postsynaptic membranes. All of this machinery is essential for Receptors that reside in the PSD of the target cell seem chemical synaptic transmission. The main demand to be primarily of the ionotropic type that are formed on this transmission is speed. The auditory system by several subunits surrounding a central ion pore. processes sound for spatial localization, identifica- Immunogold and immunoperoxidase methods dem- tion, and communication. Inherent to these functions onstrate a strong reaction for GluR2/3 and GluR4. is the ability to faithfully transmit rapid changes in Since GluR1 shows little or no immunolabeling the acoustic signals. The amino acid glutamate is the at endbulb synapses, it is inferred that most synaptic a candidate for facilitating rapid transmission. -amino-3-hydroxy-5-methyl-4-isoxazole propionic The unmistakable identification of glutamate as the acid (AMPA) receptors are composed of GluR3 and neurotransmitter of the auditory nerve has been im- GluR4 subunits. These subunits facilitate fast trans- peded by the widespread distribution of glutamate mission because of rapid desensitization. Moreover, in nervous tissue and the inability to measure its calcium permeability due to the lack of GluR2 could release during synaptic activity. As a result, research account for the rapidly decaying responses of the strategies have been to analyze the effects of pharma- postsynaptic spherical bushy cells. Immunolabeling cologic agonists and antagonists of glutamate, to study of metabotropic glutamate receptors (mGluR1a)is the properties of glutamate receptor subunits, and/or to modest at the endbulb synapse. characterize glutamate transporters. Quantitative N-Methyl-D-aspartate (NMDA) receptors feature a immunohistochemistry demonstrated greater labeling voltage-dependent calcium channel. Opening of the over primary auditory nerve endings compared to non- NMDA channel occurs as a result of depolarization primary endings (containing flat or pleomorphic syn- via the AMPA receptors. There are a number of dif- aptic vesicles) or glia. Moreover, potassium-induced ferent NMDA receptor subunits, including NR1, depolarization that depleted glutamate significantly NR2A–D, and NR3. Receptors are composed of lowered such staining in endbulb terminals. The pres- NR1 plus one or more variants of NR2, the combina- ence ofglutamate and one of its metabolic precursors tion of which determines physiological properties. in the endbulb and the complementary distribution of The role of these receptors at the endbulb synapse is glutamate receptors (GluRs) in cochlear nucleus neu- not known; they are present in the developing audi- rons represent strong inferential evidence that gluta- tory system but they diminish by weaning. mate is the neurotransmitter. The involvement of The spiking pattern of auditory neurons is deter- glutamate in auditory nerve synapses is greatly streng- mined in part by the type of voltage-sensitive potassium thened by observations that large postsynaptic channels expressed. The activation and deactivation Encyclopedia of Neuroscience (2009), vol. 1, pp. 759-770 Author's personal copy Auditory System: Giant Synaptic Terminals, Endbulbs, and Calyces 761 Physiology The time-varying nature of natural sounds requires Newborn that accurate identification depends on the ability of auditory neurons to encode timing. Vertebrates have the capacity to discriminate between pitches that dif- m fer by as little as 2 s in the period of the sound waves, and to resolve differences on the order of 10 msin the time of arrival of a sound at the two ears. The 10-day old duration of single action
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