1,721,023 research outputs found
Molecularly and structurally distinct synapses mediate reliable encoding and processing of auditory information
No full textHearing impairment is the most common human sensory deficit. Considering the sophisticated anatomy and physiology of the auditory system, disease-related failures frequently occur. To meet the demands of the neuronal circuits responsible for processing auditory information, the synapses of the lower auditory pathway are anatomically and functionally specialized to process acoustic information indefatigably with utmost temporal precision. Despite sharing some functional properties, the afferent synapses of the cochlea and of auditory brainstem differ greatly in their morphology and employ distinct molecular mechanisms for regulating synaptic vesicle release. Calyceal synapses of the endbulb of Held and the calyx of Held profit from a large number of release sites that project onto one principal cell. Cochlear inner hair cell ribbon synapses exhibit a unique one-to-one relation of the presynaptic active zone to the postsynaptic cell and use hair-cell-specific proteins such as otoferlin for vesicle release. The understanding of the molecular physiology of the hair cell ribbon synapse has been advanced by human genetics studies of sensorineural hearing impairment, revealing human auditory synaptopathy as a new nosological entity. (C) 2015 Elsevier B.V. All rights reserved
Heterogeneity of glutamatergic synapses: cellular mechanisms and network consequences
No full textChemical synapses are commonly known as a structurally and functionally highly diverse class of cell-cell contacts specialized to mediate communication between neurons. They represent the smallest “computational” unit of the brain and are typically divided into excitatory and inhibitory as well as modulatory categories. These categories are subdivided into diverse types, each representing a different structure-function repertoire that in turn are thought to endow neuronal networks with distinct computational properties. The diversity of structure and function found among a given category of synapses is referred to as heterogeneity. The main building blocks for this heterogeneity are synaptic vesicles, the active zone, the synaptic cleft, the postsynaptic density, and glial processes associated with the synapse. Each of these five structural modules entails a distinct repertoire of functions, and their combination specifies the range of functional heterogeneity at mammalian excitatory synapses, which are the focus of this review. We describe synapse heterogeneity that is manifested on different levels of complexity ranging from the cellular morphology of the pre- and postsynaptic cells toward the expression of different protein isoforms at individual release sites. We attempt to define the range of structural building blocks that are used to vary the basic functional repertoire of excitatory synaptic contacts and discuss sources and general mechanisms of synapse heterogeneity. Finally, we explore the possible impact of synapse heterogeneity on neuronal network function.Chemical synapses are commonly known as a structurally and functionally highly diverse class of cell-cell contacts specialized to mediate communication between neurons. They represent the smallest “computational” unit of the brain and are typically divided into excitatory and inhibitory as well as modulatory categories. These categories are subdivided into diverse types, each representing a different structure-function repertoire that in turn are thought to endow neuronal networks with distinct computational properties. The diversity of structure and function found among a given category of synapses is referred to as heterogeneity. The main building blocks for this heterogeneity are synaptic vesicles, the active zone, the synaptic cleft, the postsynaptic density, and glial processes associated with the synapse. Each of these five structural modules entails a distinct repertoire of functions, and their combination specifies the range of functional heterogeneity at mammalian excitatory synapses, which are the focus of this review. We describe synapse heterogeneity that is manifested on different levels of complexity ranging from the cellular morphology of the pre- and postsynaptic cells toward the expression of different protein isoforms at individual release sites. We attempt to define the range of structural building blocks that are used to vary the basic functional repertoire of excitatory synaptic contacts and discuss sources and general mechanisms of synapse heterogeneity. Finally, we explore the possible impact of synapse heterogeneity on neuronal network function
Relating structure and function of inner hair cell ribbon synapses
Get PDFIn the mammalian cochlea, sound is encoded at synapses between inner hair cells (IHCs) and type I spiral ganglion neurons (SGNs). Each SGN receives input from a single IHC ribbon-type active zone (AZ) and yet SGNs indefatigably spike up to hundreds of Hz to encode acoustic stimuli with submillisecond precision. Accumulating evidence indicates a highly specialized molecular composition and structure of the presynapse, adapted to suit these high functional demands. However, we are only beginning to understand key features such as stimulus-secretion coupling, exocytosis mechanisms, exo-endocytosis coupling, modes of endocytosis and vesicle reformation, as well as replenishment of the readily releasable pool. Relating structure and function has become an important avenue in addressing these points and has been applied to normal and genetically manipulated hair cell synapses. Here, we review some of the exciting new insights gained from recent studies of the molecular anatomy and physiology of IHC ribbon synapses
Ultrastructural maturation of the endbulb of Held active zones comparing wild-type and otoferlin-deficient mice
No full textEndbulbs of Held are located in the anteroventral cochlear nucleus and present the first central synapses of the auditory pathway. During development, endbulbs mature functionally to enable rapid and powerful synaptic transmission with high temporal precision. This process is accompanied by morphological changes of endbulb terminals. Loss of the hair cell-specific protein otoferlin (Otof) abolishes neurotransmission in the cochlea and results in the smaller endbulb of Held terminals. Thus, peripheral hearing impairment likely also leads to alterations in the morphological synaptic vesicle (SV) pool size at individual endbulb of Held active zones (AZs). Here, we investigated endbulb AZs in pre-hearing, young, and adult wild-type and Otof−/− mice. During maturation, SV numbers at endbulb AZs increased in wild-type mice but were found to be reduced in Otof−/− mice. The SV population at a distance of 0–15 nm was most strongly affected. Finally, overall SV diameters decreased in Otof−/− animals during maturation
Methods for multiscale structural and functional analysis of the mammalian cochlea
No full textThe mammalian cochlea is a snail-shaped structure deeply that is embedded in the temporal bone and harbors the auditory sensory epithelium – the organ of Corti. Since the discovery of this remarkable hearing organ in the middle of the 19th century, generations of anatomists and physiologists have been attracted to study the structural and functional details of this intricate and delicate structure and thereby contributed to establishing our current understanding of peripheral sound encoding. Since these early days, the continued development of novel imaging technologies – both on light and electron microscopic level – has driven the auditory research field and now enables the visualization of cochlear structures across multiple scales with unprecedented clarity and exquisite detail. To honor these achievements, this review aims to provide a concise overview of current multi-scale imaging methodologies to investigate cochlear anatomy and cellular function in the peripheral auditory pathway. For this purpose, we will outline the technological concepts underlying these techniques – ranging from label-free to label-containing approaches – highlight their respective strengths and limitations and provide specific examples of their use in modern auditory research. We will focus on traditional as well as less conventional imaging techniques that present essential tools for unraveling the protein composition, nanoscale assembly, and physiology of the first auditory synapse and associated structures. In addition, we will introduce novel non-invasive large-scale methodologies that allow for high-resolution in situ imaging of the structurally-unperturbed cochlea and point out potential future applications. In combination, these techniques allow for a comprehensive multi-scale analysis of cochlear structure and function
Piccolo Promotes Vesicle Replenishment at a Fast Central Auditory Synapse
Get PDFPiccolo and Bassoon are the two largest cytomatrix of the active zone (CAZ) proteins involved in scaffolding and regulating neurotransmitter release at presynaptic active zones (AZs), but have long been discussed as being functionally redundant. We employed genetic manipulation to bring forth and segregate the role of Piccolo from that of Bassoon at central auditory synapses of the cochlear nucleus—the endbulbs of Held. These synapses specialize in high frequency synaptic transmission, ideally poised to reveal even subtle deficits in the regulation of neurotransmitter release upon molecular perturbation. Combining semi-quantitative immunohistochemistry, electron microscopy, and in vitro and in vivo electrophysiology we first studied signal transmission in Piccolo-deficient mice. Our analysis was not confounded by a cochlear deficit, as a short isoform of Piccolo (“Piccolino”) present at the upstream ribbon synapses of cochlear inner hair cells (IHC), is unaffected by the mutation. Disruption of Piccolo increased the abundance of Bassoon at the AZs of endbulbs, while that of RIM1 was reduced and other CAZ proteins remained unaltered. Presynaptic fiber stimulation revealed smaller amplitude of the evoked excitatory postsynaptic currents (eEPSC), while eEPSC kinetics as well as miniature EPSCs (mEPSCs) remained unchanged. Cumulative analysis of eEPSC trains indicated that the reduced eEPSC amplitude of Piccolo-deficient endbulb synapses is primarily due to a reduced readily releasable pool (RRP) of synaptic vesicles (SV), as was corroborated by a reduction of vesicles at the AZ found on an ultrastructural level. Release probability seemed largely unaltered. Recovery from short-term depression was slowed. We then performed a physiological analysis of endbulb synapses from mice which, in addition to Piccolo deficiency, lacked one functional allele of the Bassoon gene. Analysis of the double-mutant endbulbs revealed an increase in release probability, while the synapses still exhibited the reduced RRP, and the impairment in SV replenishment was exacerbated. We propose additive roles of Piccolo and Bassoon in SV replenishment which in turn influences the organization and size of the RRP, and an additional role of Bassoon in regulation of release probability
Tubular microdomains of Rab7-positive endosomes retrieve TrkA, a mechanism disrupted in Charcot-Marie-Tooth disease 2B
No full textAxonal survival and growth requires signalling from tropomyosin receptor kinases (Trks). To transmit their signals, receptor-ligand complexes are endocytosed and undergo retrograde trafficking to the soma, where downstream signalling occurs. Vesicles transporting neurotrophic receptors to the soma are reported to be Rab7-positive late endosomes and/or multivesicular bodies (MVBs), where receptors localize within so-called intraluminal vesicles (herein Rab7 corresponds to Rab7A unless specified otherwise). Therefore, one challenging question is how downstream signalling is possible given the insulating properties of intraluminal vesicles. In this study, we report that Rab7-positive endosomes and MVBs retrieve TrkA (also known as NTRK1) through tubular microdomains. Interestingly, this phenotype is absent for the EGF receptor. Furthermore, we found that endophilinA1, endophilinA2 and endophilinA3, together with WASH1 (also known as WASHC1), are involved in the tubulation process. In Charcot-Marie-Tooth disease 2B (CMT2B), a neuropathy of the peripheral nervous system, this tubulating mechanism is disrupted. In addition, the ability to tubulate correlates with the phosphorylation levels of TrkA as well as with neurite length in neuronal cultures from dorsal root ganglia. In all, we report a new retrieval mechanism of late Rab7-positive endosomes, which enables TrkA signalling and sheds new light onto how neurotrophic signalling is disrupted in CMT2B. This article has an associated First Person interview with the first author of the paper
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