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PubMed2006

SynDB: a Synapse protein DataBase based on synapse ontology.

A synapse is the junction across which a nerve impulse passes from an axon terminal to a neuron, muscle cell or gland cell. The functions and building molecules of the synapse are essential to almost all neurobiological processes. To describe synaptic structures and functions, we have developed Synapse Ontology (SynO), a hierarchical representation that includes 177 terms with hundreds of synonyms and branches up to eight levels deep. associated 125 additional protein keywords and 109 InterPro domains with these SynO terms. Using a combination of automated keyword searches, domain searches and manual curation, we collected 14,000 non-redundant synapse-related proteins, including 3000 in human. We extensively annotated the proteins with information about sequence, structure, function, expression, pathways, interactions and disease associations and with hyperlinks to external databases. The data are stored and presented in the Synapse protein DataBase (SynDB, http://syndb.cbi.pku.edu.cn). SynDB can be interactively browsed by SynO, Gene Ontology (GO), domain families, species, chromosomal locations or Tribe-MCL clusters. It can also be searched by text (including Boolean operators) or by sequence similarity. SynDB is the most comprehensive database to date for synaptic proteins.

Animals↗
PubMed2005

Diminished neuronal activity increases neuron-neuron connectivity underlying silent synapse formation and the rapid conversion of silent to functional synapses.

Neuronal activity regulates the synaptic strength of neuronal networks. However, it is still unclear how diminished activity changes connection patterns in neuronal circuits. To address this issue, we analyzed neuronal connectivity and relevant mechanisms using hippocampal cultures in which developmental synaptogenesis had occurred. We show that diminution of network activity in mature neuronal circuit promotes reorganization of neuronal circuits via NR2B subunit-containing NMDA-type glutamate receptors (NR2B-NMDARs), which mediate silent synapse formation. Simultaneous double whole-cell recordings revealed that diminishing neuronal circuit activity for 48 h increased the number of synaptically connected neuron pairs with both silent and functional synapses. This increase was accompanied by the specific expression of NR2B-NMDARs at synaptic sites. Analysis of miniature EPSCs (mEPSCs) showed that the frequency of NMDAR-mediated, but not AMPAR-mediated, mEPSCs increased, indicating that diminished neuronal activity promotes silent synapse formation via the surface delivering NR2B-NMDARs in mature neurons. After activation of neuronal circuit by releasing from TTX blockade (referred as circuit reactivation), the frequency of AMPAR-mediated mEPSCs increased instead, and this increase was prevented by ifenprodil. The circuit reactivation also caused an increased colocalization of glutamate receptor 1-specfic and synaptic NR2B-specific puncta. These results indicate that the circuit reactivation converts rapidly silent synapses formed during activity suppression to functional synapses. These data may provide a new example of homeostatic circuit plasticity that entails the modulation of neuron-neuron connectivity by synaptic activity.

2-Amino-5-phosphonovalerate↗
PubMed1999

Synaptic plasticity at thalamocortical synapses in developing rat somatosensory cortex: LTP, LTD, and silent synapses.

Thalamocortical synaptic transmission in the rat's primary somatosensory (S1) cortex is modified by sensory experience during a critical period early in life. Despite the importance of such plasticity for the maturation of thalamocortical circuits, the synaptic basis of this plasticity is unknown. Here, we review evidence suggesting that long-term potentiation and depression (LTP and LTD) of thalamocortical synaptic transmission may be involved in this plasticity. In an in vitro slice preparation, thalamocortical synaptic responses exhibit N-methyl-D-aspartate (NMDA) receptor-dependent LTP and LTD during a developmental period similar to the critical period in vivo. The inability to induce LTP and LTD after the critical period may result in part from a developmental reduction in the duration of NMDA receptor currents. In addition, during the critical period many thalamocortical synapses exhibit NMDA receptor currents but no detectable AMPA receptor currents, and thus may be functionally silent at resting membrane potentials. LTP converts silent synapses to functional ones by causing the rapid appearance of AMPA currents. These observations suggest that thalamocortical synapses may be formed as silent synapses which are subsequently made functional by LTP. LTP and LTD may then regulate the efficacy of these functional synapses and thereby contribute to experience-dependent changes in S1 thalamocortical circuits.

Animals↗
PubMed1992

Morphological comparison by scanning electron microscopy of transient retina-muscle synapses and long-lived spinal cord-muscle synapses.

Retinal neurons will form cholinergic synapses on muscle cells in tissue culture, however, these inappropriate synapses are transient. Although within 24 hrs. myotubes are readily innervated, by 7 days of coculture no physiological response can be detected. In contrast, spinal cord neurons form long-lived synapses on muscle cells which can be detected for several weeks. In this study, we examined retina-muscle and spinal cord-muscle cocultures to determine whether retinal neurons withdrew their processes from muscle cells, and preferentially maintained contacts on other retinal neurons. Using scanning electron microscopy, we observed that during the first 24 hrs. of coculture both types of neurons extend processes along myotubes. The neurite outgrowth occurs concomitantly with the observed increase in physiologically detected synaptic muscle responses. Over the next 6 days, retinal neurite contacts on the muscle cells are withdrawn, while spinal cord contacts remain. Retinal neurons remain in contact with other retinal neurons at day 7 of coculture. Thus, retinal neurons form and maintain synapses on their appropriate target (other retinal neurons); whereas, they withdraw contacts from inappropriate targets (muscle cells). By contrasting retinal and spinal cord synapses on muscle cells, we hope to elucidate the mechanisms of synaptic recognition and maintenance.

Animals↗
PubMed1989

Normal numbers of retinotectal synapses during the activity-sensitive period of optic regeneration in goldfish: HRP-EM evidence implicating synapse rearrangement and collateral elimination during map refinement.

Optic and nonoptic fibers and synapses were counted in the primary optic innervation layer (S-SO-SFGS) in anteromedial tectum in normal goldfish and in fish 30, 60, and 240 d after the optic nerve was crushed. A newly developed "cold-fill" HRP-labeling protocol was used to label optic afferents for electron microscopy, and counts were then made on EM photomontages of columns through the HRP-labeled S-SO-SFGS. Normal numbers of retinotectal synapses were present at 30 d regeneration, at a time when activity-dependent refinement of the optic projection is incomplete. Normal numbers were also found at 60 and 240 d, when refinement is largely completed. In contrast to this constancy in optic synapse numbers, there was nearly 10 times the normal number of optic fibers in the SFGS at 30 d, and these were reduced by 50% at 60 d, remaining over 4 times normal at 240 d. These findings imply extensive rearrangement of optic synapses during map refinement. They also indicate that synapse rearrangement is associated with the elimination of optic collaterals.

Animals↗
PubMed1996

Organization of AMPA receptor subunits at a glutamate synapse: a quantitative immunogold analysis of hair cell synapses in the rat organ of Corti.

Sensitive and high-resolution immunocytochemical procedures were used to investigate the spatial organization of AMPA receptor subunits (GluR1-4) at the synapse between the inner hair cells and the afferent dendrites in the rat organ of Corti. This is a synapse with special functional properties and with a presynaptic dense body that defines the center of the synapse and facilitates its morphometric analysis. A quantitative postembedding immunocytochemical analysis was performed on specimens that had been embedded in a metachrylate resin at low temperature after freeze substitution. Single- and double-labeling procedures indicated that GluR2/3 and GluR4 subunits were colocalized throughout the postsynaptic density, with a maximum distance of 300 nm from the presynaptic body and with higher concentrations peripherally than centrally. No receptor immunolabeling was found at extrasynaptic membranes, but some GluR4 subunits appeared to be expressed presynaptically. The synapses between outer hair cells and afferent dendrites were devoid of labeling. The present data indicate that AMPA receptor subunits are inserted into the postsynaptic membrane in a very precise manner and that their density increases on moving away from the center of the synapse.

Animals↗
PubMed1997

Design and functional specification of the Synapses federated healthcare record server. Synapses Consortium.

Synapses is a project funded under the EU Health Telematics Framework IV Programme. Synapses sets out to solve problems of sharing data between autonomous information systems, by providing generic and open means to combine healthcare records or dossiers consistently, simply, comprehensibly and securely, whether the data passes within a single healthcare institution or between institutions. This paper presents the specification of the Synapses server, the kernel concept of Synapses. It describes the basis in the European prestandard for Electronic Healthcare Record Architecture, the interfaces to the Synapses server and different integration mechanisms for systems providing information to the server. The specification will be verified at a number of validation sites, and the final result will be in the public domain.

Computer Systems↗
PubMed2001

Localization of glutamate receptors at a complex synapse. The mammalian photoreceptor synapse.

A key feature of signal processing in the mammalian retina is parallel processing, where the segregation of visual information, e.g., brightness, darkness, and color, starts at the first synapse in the retina, the photoreceptor synapse. These various aspects are transmitted in parallel from the input neurons of the retina, the photoreceptor cells, through the interconnecting bipolar cells, to the output neurons, the ganglion cells. The photoreceptors and bipolar cells release a single excitatory neurotransmitter, glutamate, at their synapses. This parsimony is contrasted by the expression of a plethora of glutamate receptors, receptor subunits, and isoforms. The detailed knowledge of the synaptic distribution of glutamate receptors thus is of major importance in understanding the mechanisms of retinal signal processing. This review intends to highlight recent studies on the distribution of glutamate receptors at the photoreceptor synapses of the mammalian retina.

Animals↗
PubMed1989

Commissural synapses, but not mossy fiber synapses, in hippocampal field CA3 exhibit associative long-term potentiation and depression.

When CA3 commissural afferents received low-frequency (weak) stimuli synchronized with a train of mossy fiber bursts (strong), associative long-term potentiation (LTP) was induced at mixed commissural and associational synapses on hippocampal CA3 pyramidal cells in vitro. In contrast, a weak mossy fiber input did not potentiate when given in phase with commissural/associational bursts. Furthermore, commissural/associational synapses receiving low-frequency stimuli out-of-phase with strong rhythmic mossy fiber input showed associative long-term depression (LTD), whereas mossy fiber synaptic strengths were not depressed when they received weak inputs out-of-phase with a strong commissural/associational input. Thus, both associative LTP and associative LTD can be induced at commissural/associational synapses, but not at mossy fiber synapses.

Action Potentials↗
PubMedDate not supplied

Activity-dependent switch from synapse formation to synapse elimination during development of neuromuscular junctions.

The embryonic development of neuromuscular junctions consists of two successive epochs, an early period marked by exuberant synapse formation and a later period marked by synapse elimination. In the frog muscles we have studied, myogenesis is protracted and overlaps the periods of synapse formation and elimination. Thus, the formative and regressive events of synaptic development do not occur in synchrony across different fibers in the muscle. We propose that local activity orchestrates a shift from synaptogenesis to synapse elimination at the level of single muscle fibers. We also present evidence that perisynaptic Schwann cells and the expression of ion channels in the sarcolemma play important roles in the development of neuromuscular junctions. Questions for future study are outlined.

Action Potentials↗
PubMed2004

Optical quantal analysis indicates that long-term potentiation at single hippocampal mossy fiber synapses is expressed through increased release probability, recruitment of new release sites, and activation of silent synapses.

It is generally believed that long-term potentiation (LTP) at hippocampal mossy fiber synapses between dentate granule and CA3 pyramidal cells is expressed through presynaptic mechanisms leading to an increase in quantal content. The source of this increase has remained undefined but could include enhanced probability of transmitter release at existing functional release sites or increases in the number of active release sites. We performed optical quantal analyses of transmission at individual mossy fiber synapses in cultured hippocampal slices, using confocal microscopy and intracellular fluorescent Ca(2+) indicators. Our results indicate that LTP is expressed at functional synapses by both increased probability of transmitter release and recruitment of new release sites, including the activation of previously silent synapses here visualized for the first time.

Animals↗
PubMedDate not supplied

[Three-dimentional organization of synapses and astroglia in the hippocampus of rats and ground squirrels: new structural and functional paradigms of the synapse function].

The literature data and our own data on the synaptic plasticity and remodeling of synaptic organelles in the central nervous system are reviewed. Modern techniques of laser scanning confocal microscopy and serial thin sectioning for in vivo and in vitro studies of dendritic spines, including the relationship between morphological changes and the efficacy of synaptic transmission, are discussed using, in particular, a model of long-term potentiation. The organization of dendritic spines and postsynaptic densities of different categories as well as the role of filopodia in spine genesis were analyzed. It was shown that the method of serial ultrathin sections is the most effective for unbiased quantitative stereological analysis and 3D reconstructions. By using the refined method of serial ultrathin sections with subsequent three-dimensional reconstructions, the presence of giant mitochondria in hippocampal neuronal dendrites was demonstrated. It was shown that smooth endoplasmic reticulum forms a unified continuum with the outer membrane of the mitochondrial envelope within dendrites. It was suggested that this continuum provides calcium tunneling, which makes possible intracellular signal transduction during synaptic transmission. Evidence is presented indicating the presence of gap junctions ("electrical synapses") in the synapses of mammalian brain, as well as between glial processes, and between glial cells and neurons. Our data and the data of other authors show that glial cell processes form a structural and functional glial network, which modulates the functioning of the neuronal network. The connection of dendritic spines with the glial network is shown on 3D reconstructions by analyzing the neuropil volume in CA1 hippocampal area of ground squirrels in three functional states: normothermia, provoked arousal, and hibernation when brain temperature falls below 6 degrees C. The own data of the authors are discussed indicating the formation of more than five presynaptic boutons (multiple synapses) on both CA1 mushroom-like dendritic spines and CA3 thorny excrescences. On the basis of the analysis, new ideas of the organization and functioning of synapses were suggested.

Animals↗
PubMed1996

A molecular mechanism for synapse elimination: novel inhibition of locally generated thrombin delays synapse loss in neonatal mouse muscle.

Activity-dependent, polyneuronal synapse elimination (ADPSE) is a programmed, regressive event in the development of the nervous system and readily studied at the neuromuscular junction, where it is complete 15-20 days after birth. Local excess, or imbalanced, protease activity is one of several possible underlying mechanisms. In this regard, thrombin mediates activity-dependent synapse loss in an in vitro model of ADPSE. To test the involvement of thrombin in vivo, we locally applied the leech thrombin-specific inhibitor, hirudin. We monitored neuromuscular behavior, correlated with acetylcholinesterase and silver nitrate histochemistry at endplates, for changes in the timecourse of in vivo synapse elimination and assayed both thrombin activity and prothrombin expression in developing muscle. Hirudin retarded elimination, without altering motor performance, uniquely at Postnatal Day 5 (P5) and maximally at P9. Reverse transcription-polymerase chain reaction (PCR) showed that neonatal muscle was a source of local prothrombin, with peak expression during the first week after birth. A specific chromogenic assay revealed that local thrombin, activated from muscle-derived prothrombin, peaked during maximal synapse remodeling.

Animals↗
PubMed2005

HIV-1 trafficking to the dendritic cell-T-cell infectious synapse uses a pathway of tetraspanin sorting to the immunological synapse.

Dendritic cells (DCs) are essential components of the early events of HIV infection. Here, we characterized the trafficking pathways that HIV-1 follows during its capture by DCs and its subsequent presentation to CD4(+) T cells via an infectious synapse. Immunofluorescence microscopy indicates that the virus-containing compartment in mature DCs (mDCs) co-labels for the tetraspanins CD81, CD82, and CD9 but contains little CD63 or LAMP-1. Using ratio imaging of pH-reporting fluorescent virions in live DCs, we show that HIV-1 is internalized in an intracellular endocytic compartment with a pH of 6.2. Significantly, we demonstrate that the infectivity of cell-free virus is more stable at mildly acidic pH than at neutral pH. Using electron microscopy, we confirm that HIV-1 accumulates in intracellular vacuoles that contain CD81 positive internal membranes but overlaps only partially with CD63. When allowed to contact T cells, HIV-1-loaded DCs redistribute CD81, and CD9, as well as internalized HIV-1, but not the immunological synapse markers MHC-II and T-cell receptor to the infectious synapse. Together, our results indicate that HIV-1 is internalized into a non-conventional, non-lysosomal, endocytic compartment in mDCs and further suggest that HIV-1 is able to selectively subvert components of the intracellular trafficking machinery required for formation of the DC-T-cell immunological synapse to facilitate its own cell-to-cell transfer and propagation.

Antigens, CD↗
PubMed1995

Synapse elimination, the size principle, and Hebbian synapses.

Synapse elimination at the vertebrate neuromuscular junction reduces a polyinnervated population of muscle fibers to a monoinnervated state. The function of this developmental phenomenon (if any) is unproven. A theoretical analysis of Hebbian (correlation) rules connecting presynaptic and postsynaptic activity and synaptic strength at the neuromuscular junction is presented. The following points are demonstrated: (1) Correlational competition leads to the reduction of polyinnervation to a stable monoinnervated state; (2) the competition gives rise to the size principle over a wide range of the plausible parameter space; (3) over a significant subrange, the competition selectively eliminates topographically incorrect synapses; and (4) in cases in which topographic projection errors overwhelm the system, both error correction and the development of the size principle are disrupted. Correlational competition may explain contradictory experimental results concerning the effects of stimulating or silencing subpopulations of motor neurons. It may also explain an otherwise puzzling instance of a breakdown in the size principle seen in humans undergoing neural regeneration. Taken together, these findings suggest a novel hypothesis for the function of synapse elimination at the neuromuscular junction: the establishment of the size principle.

Models, Neurological↗
PubMed1997

Synapse-specific, long-term facilitation of aplysia sensory to motor synapses: a function for local protein synthesis in memory storage.

The requirement for transcription during long-lasting synaptic plasticity has raised the question of whether the cellular unit of synaptic plasticity is the soma and its nucleus or the synapse. To address this question, we cultured a single bifurcated Aplysia sensory neuron making synapses with two spatially separated motor neurons. By perfusing serotonin onto the synapses made onto one motor neuron, we found that a single axonal branch can undergo long-term branch-specific facilitation. This branch-specific facilitation depends on CREB-mediated transcription and involves the growth of new synaptic connections exclusively at the treated branch. Branch-specific long-term facilitation requires local protein synthesis in the presynaptic but not the postsynaptic cell. In fact, presynaptic sensory neuron axons deprived of their cell bodies are capable of protein synthesis, and this protein synthesis is stimulated 3-fold by exposure to serotonin.

Animals↗
PubMed2002

Glycobiology of the synapse: the role of glycans in the formation, maturation, and modulation of synapses.

Synapses, which are the fundamental functional unit of the nervous system, are considered to be highly specialized cell adhesion structures. Studies since the 1960s demonstrated that various carbohydrates and glycoproteins are expressed in synapses in the central and peripheral nervous system. Although the functional roles of these synaptic carbohydrates and glycoproteins remain to be determined, rapidly accumulating data suggest that they may play critical roles in the formation, maturation, and functional modulation of synapses.

Agrin↗
PubMed1998

Modulation of reconstructed peptidergic synapses and electrical synapses by general anaesthetics.

1. The actions of clinically relevant concentrations of general anaesthetics on reconstructed peptidergic synapses and electrical synapses in the intact brain of the mollusc Lymnaea stagnalis (L.) are described. 2. At identified, reconstructed, FMRFamidergic synapses, chemical synaptic transmission is completely blocked in 2% halothane. 3. Inhibitory postsynaptic responses to directly applied FMRFamide are maintained in 2% halothane and are enhanced in 1% halothane, unlike excitatory responses which are abolished at this concentration. 4. Met-enkephalin normally produces inhibitory responses on postsynaptic PeA neurones, but these are non-reversibly abolished by halothane, whose presence induces novel, dose-dependent, enkephalinergic depolarising responses. 5. The biophysical effects of volatile anaesthetics and sodium pentobarbital on neuronal membranes have been described and they are shown to have opposite dose-dependent effects on input resistance, input conductance and time constant of the electrically coupled neurones VD1 and RPD2. 6. Volatile anaesthetics decouple the neurones VD1 and RPD2 in a dose dependent manner, whilst sodium pentobarbital either enhances coupling or has no effect, depending on the concentration used.

Anesthetics, General↗