Diffusional trapping of GluR1 AMPA receptors by input-specific synaptic activity

Synaptic activity regulates the postsynaptic accumulation of AMPA receptors over timescales ranging from minutes to days. Indeed, the regulated trafficking and mobility of GluR1 AMPA receptors underlies many forms of synaptic potentiation at glutamatergic synapses throughout the brain. However, the basis for synapse-specific accumulation of GluR1 is unknown. Here we report that synaptic activity locally immobilizes GluR1 AMPA receptors at individual synapses. Using single-molecule tracking together with the silencing of individual presynaptic boutons, we demonstrate that local synaptic activity reduces diffusional exchange of GluR1 between synaptic and extraynaptic domains, resulting in postsynaptic accumulation of GluR1. At neighboring inactive synapses, GluR1 is highly mobile with individual receptors frequently escaping the synapse. Within the synapse, spontaneous activity confines the diffusional movement of GluR1 to restricted subregions of the postsynaptic membrane. Thus, local activity restricts GluR1 mobility on a submicron scale, defining an input-specific mechanism for regulating AMPA receptor composition and abundance.     

Learning in spiking neural networks by reinforcement of stochastic synaptic transmission

It is well-known that chemical synaptic transmission is an unreliable process, but the function of such unreliability remains unclear. Here I consider the hypothesis that the randomness of synaptic transmission is harnessed by the brain for learning, in analogy to the way that genetic mutation is utilized by Darwinian evolution. This is possible if synapses are "hedonistic," responding to a global reward signal by increasing their probabilities of vesicle release or failure, depending on which action immediately preceded reward. Hedonistic synapses learn by computing a stochastic approximation to the gradient of the average reward. They are compatible with synaptic dynamics such as short-term facilitation and depression and with the intricacies of dendritic integration and action potential generation. A network of hedonistic synapses can be trained to perform a desired computation by administering reward appropriately, as illustrated here through numerical simulations of integrate-and-fire model neurons.     

LTD windows of the STDP learning rule and synaptic connections having a large transmission delay enable robust sequence learning amid background noise

Spike-timing-dependent synaptic plasticity (STDP) is a simple and effective learning rule for sequence learning. However, synapses being subject to STDP rules are readily influenced in noisy circumstances because synaptic conductances are modified by pre- and postsynaptic spikes elicited within a few tens of milliseconds, regardless of whether those spikes convey information or not. Noisy firing existing everywhere in the brain may induce irrelevant enhancement of synaptic connections through STDP rules and would result in uncertain memory encoding and obscure memory patterns. We will here show that the LTD windows of the STDP rules enable robust sequence learning amid background noise in cooperation with a large signal transmission delay between neurons and a theta rhythm, using a network model of the entorhinal cortex layer II with entorhinal-hippocampal loop connections. The important element of the present model for robust sequence learning amid background noise is the symmetric STDP rule having LTD windows on both sides of the LTP window, in addition to the loop connections having a large signal transmission delay and the theta rhythm pacing activities of stellate cells. Above all, the LTD window in the range of positive spike-timing is important to prevent influences of noise with the progress of sequence learning.     

Neurotransmission: emerging roles of endocannabinoids

Postsynaptic release of endocannabinoids can inhibit presynaptic neurotransmitter release on short and long timescales. This retrograde inhibition occurs at both excitatory and inhibitory synapses and may provide a mechanism for synaptic gain control, short-term associative plasticity, reduction of synaptic crosstalk, and metaplasticity.     

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.     

Mathematical Modeling of Sustainable Synaptogenesis by Repetitive Stimuli Suggests Signaling Mechanisms In Vivo

The mechanisms of long-term synaptic maintenance are a key component to understanding the mechanism of long-term memory. From biological experiments, a hypothesis arose that repetitive stimuli with appropriate intervals are essential to maintain new synapses for periods of longer than a few days. We successfully reproduce the time-course of relative numbers of synapses with our mathematical model in the same conditions as biological experiments, which used Adenosine-3′, 5′-cyclic monophosphorothioate, Sp-isomer (Sp-cAMPS) as external stimuli. We also reproduce synaptic maintenance responsiveness to intervals of Sp-cAMPS treatment accompanied by PKA activation. The model suggests a possible mechanism of sustainable synaptogenesis which consists of two steps. First, the signal transduction from an external stimulus triggers the synthesis of a new signaling protein. Second, the new signaling protein is required for the next signal transduction with the same stimuli. As a result, the network component is modified from the first network, and a different signal is transferred which triggers the synthesis of another new signaling molecule. We refer to this hypothetical mechanism as network succession. We build our model on the basis of two hypotheses: (1) a multi-step network succession induces downregulation of SSH and COFILIN gene expression, which triggers the production of stable F-actin; (2) the formation of a complex of stable F-actin with Drebrin at PSD is the critical mechanism to achieve long-term synaptic maintenance. Our simulation shows that a three-step network succession is sufficient to reproduce sustainable synapses for a period longer than 14 days. When we change the network structure to a single step network, the model fails to follow the exact condition of repetitive signals to reproduce a sufficient number of synapses. Another advantage of the three-step network succession is that this system indicates a greater tolerance of parameter changes than the single step network.     

Relative Contributions of Specific Activity Histories and Spontaneous Processes to Size Remodeling of Glutamatergic Synapses

The idea that synaptic properties are defined by specific pre- and postsynaptic activity histories is one of the oldest and most influential tenets of contemporary neuroscience. Recent studies also indicate, however, that synaptic properties often change spontaneously, even in the absence of specific activity patterns or any activity whatsoever. What, then, are the relative contributions of activity history-dependent and activity history-independent processes to changes synapses undergo? To compare the relative contributions of these processes, we imaged, in spontaneously active networks of cortical neurons, glutamatergic synapses formed between the same axons and neurons or dendrites under the assumption that their similar activity histories should result in similar size changes over timescales of days. The size covariance of such commonly innervated (CI) synapses was then compared to that of synapses formed by different axons (non-CI synapses) that differed in their activity histories. We found that the size covariance of CI synapses was greater than that of non-CI synapses; yet overall size covariance of CI synapses was rather modest. Moreover, momentary and time-averaged sizes of CI synapses correlated rather poorly, in perfect agreement with published electron microscopy-based measurements of mouse cortex synapses. A conservative estimate suggested that ~40% of the observed size remodeling was attributable to specific activity histories, whereas ~10% and ~50% were attributable to cell-wide and spontaneous, synapse-autonomous processes, respectively. These findings demonstrate that histories of naturally occurring activity patterns can direct glutamatergic synapse remodeling but also suggest that the contributions of spontaneous, possibly stochastic, processes are at least as great.     

Spectral analysis of input spike trains by spike-timing-dependent plasticity

Spike-timing-dependent plasticity (STDP) has been observed in many brain areas such as sensory cortices, where it is hypothesized to structure synaptic connections between neurons. Previous studies have demonstrated how STDP can capture spiking information at short timescales using specific input configurations, such as coincident spiking, spike patterns and oscillatory spike trains. However, the corresponding computation in the case of arbitrary input signals is still unclear. This paper provides an overarching picture of the algorithm inherent to STDP, tying together many previous results for commonly used models of pairwise STDP. For a single neuron with plastic excitatory synapses, we show how STDP performs a spectral analysis on the temporal cross-correlograms between its afferent spike trains. The postsynaptic responses and STDP learning window determine kernel functions that specify how the neuron "sees" the input correlations. We thus denote this unsupervised learning scheme as 'kernel spectral component analysis' (kSCA). In particular, the whole input correlation structure must be considered since all plastic synapses compete with each other. We find that kSCA is enhanced when weight-dependent STDP induces gradual synaptic competition. For a spiking neuron with a "linear" response and pairwise STDP alone, we find that kSCA resembles principal component analysis (PCA). However, plain STDP does not isolate correlation sources in general, e.g., when they are mixed among the input spike trains. In other words, it does not perform independent component analysis (ICA). Tuning the neuron to a single correlation source can be achieved when STDP is paired with a homeostatic mechanism that reinforces the competition between synaptic inputs. Our results suggest that neuronal networks equipped with STDP can process signals encoded in the transient spiking activity at the timescales of tens of milliseconds for usual STDP.     

Neural Organization of the Median Ocellus of the Dragonfly : II. Synaptic structure

Two types of presumed synaptic contacts have been recognized by electron microscopy in the synaptic plexus of the median ocellus of the dragonfly. The first type is characterized by an electron-opaque, button-like organelle in the presynaptic cytoplasm, surrounded by a cluster of synaptic vesicles. Two postsynaptic elements are associated with these junctions, which we have termed button synapses. The second synaptic type is characterized by a dense cluster of synaptic vesicles adjacent to the presumed presynaptic membrane. One postsynaptic element is observed at these junctions. The overwhelming majority of synapses seen in the plexus are button synapses. They are found most commonly in the receptor cell axons where they synaptically contact ocellar nerve dendrites and adjacent receptor cell axons. Button synapses are also seen in the ocellar nerve dendrites where they appear to make synapses back onto receptor axon terminals as well as onto adjacent ocellar nerve dendrites. Reciprocal and serial synaptic arrangements between receptor cell axon terminals, and between receptor cell axon terminals and ocellar nerve dendrites are occasionally seen. It is suggested that the lateral and feedback synapses in the median ocellus of the dragonfly play a role in enhancing transients in the postsynaptic responses.     

Transmission,Development, and Plasticity of Synapses

Chemical synapses are sites of contact and information transfer between a neuron and its partner cell. Each synapse is a specialized junction, where the presynaptic cell assembles machinery for the release of neurotransmitter, and the postsynaptic cell assembles components to receive and integrate this signal. Synapses also exhibit plasticity, during which synaptic function and/or structure are modified in response to activity. With a robust panel of genetic, imaging, and electrophysiology approaches, and strong evolutionary conservation of molecular components, Drosophila has emerged as an essential model system for investigating the mechanisms underlying synaptic assembly, function, and plasticity. We will discuss techniques for studying synapses in Drosophila, with a focus on the larval neuromuscular junction (NMJ), a well-established model glutamatergic synapse. Vesicle fusion, which underlies synaptic release of neurotransmitters, has been well characterized at this synapse. In addition, studies of synaptic assembly and organization of active zones and postsynaptic densities have revealed pathways that coordinate those events across the synaptic cleft. We will also review modes of synaptic growth and plasticity at the fly NMJ, and discuss how pre- and postsynaptic cells communicate to regulate plasticity in response to activity.     

Modeling Signal Transduction Leading to Synaptic Plasticity: Evaluation and Comparison of Five Models

An essential phenomenon of the functional brain is synaptic plasticity which is associated with changes in the strength of synapses between neurons. These changes are affected by both extracellular and intracellular mechanisms. For example, intracellular phosphorylation-dephosphorylation cycles have been shown to possess a special role in synaptic plasticity. We, here, provide the first computational comparison of models for synaptic plasticity by evaluating five models describing postsynaptic signal transduction networks. Our simulation results show that some of the models change their behavior completely due to varying total concentrations of protein kinase and phosphatase. Furthermore, the responses of the models vary when models are compared to each other. Based on our study, we conclude that there is a need for a general setup to objectively compare the models and an urgent demand for the minimum criteria that a computational model for synaptic plasticity needs to meet.     

The formation of synapses in the central nervous system

Interneuronal synapses are specialized contact zones formed between the transmitting pole of one neuron, usually an axon, and the receptive pole of another nerve cell, usually a dendritic process or the soma. The formation of these synaptic contacts is the result of cellular events related to neurite elongation, the establishment of polarity, axon guidance, and target recognition. A series of morphological rearrangements takes place once synaptic targets establish their initial contact. These changes include the clustering of synaptic vesicles in the presynaptic element and the formation of a specialized area capable of signal transduction at the postsynaptic target. The present review discusses the role of different synaptic proteins in the cellular events leading to the formation of synapses among neurons in the central nervous system.     

Pattern of synaptic connections in the pineal organ of the ayu,Plecoglossus altivelis (Teleostei)

Summary Synaptic connections were studied by means of electron microscopy in the sensory pineal organ of the ayu, Plecoglossus altivelis, a highly photosensitive teleost species. Three types of specific contacts were observed in the pineal end-vesicle: 1) symmetrically organized gap junctions between the basal processes of adjacent photoreceptor cells; 2) sensory synapses endowed with synaptic ribbons, formed by basal processes of photoreceptor cells and dendrites of pineal neurons; 3) conventional synapses between pineal neurons, containing both clear and dense-core vesicles at the presynaptic site. Based on these findings, the following interpretations are given: (i) The gap junctions may be involved in an enhancement of electric communication and signal encoding between pineal photoreceptor cells. (ii) The sensory synapses transmit photic signals from the photoreceptor cells to pineal nerve cells. (iii) The conventional synapses are assumed to be involved in a lateral interaction and/or summation of information in the sensory pineal organ. A concept of synaptic relationships among the sensory and neuronal elements in the pineal organ of the ayu is presented.Fellow of the Alexander von Humboldt Foundation, Federal Republic of Germany     

Synapses identifiable in the parietal ganglia of the snail Helix lucorum

The synaptic plasticity is a background for learning and memory. Identifiable synapses that are the synapses between individually identifiable neurons are a very convenient model for studying plasticity. Synapses between the interoceptive mechanosensory neurons and the command neurons of the withdrawal behavior were identified in the Helix lucorum brain. It was shown that synaptic plasticity estimated by the dynamics of the elementary postsynaptic potentials elicited by single presynaptic spikes differed from the synaptic plasticity estimated by the dynamics of compound synaptic responses of the same neurons to sensory stimulation. Habituation and heterosynaptic facilitation phenomena are discussed in terms of the dynamics of the elementary postsynaptic potentials.     

Signal regulatory proteins (SIRPS) are secreted presynaptic organizing molecules

Formation of chemical synapses requires exchange of organizing signals between the synaptic partners. Using synaptic vesicle aggregation in cultured neurons as a marker of presynaptic differentiation, we purified candidate presynaptic organizers from mouse brain. A major bioactive species was the extracellular domain of signal regulatory protein alpha (SIRP-alpha), a transmembrane immunoglobulin superfamily member concentrated at synapses. The extracellular domain of SIRP-alpha is cleaved and shed in a developmentally regulated manner. The presynaptic organizing activity of SIRP-alpha is mediated in part by CD47. SIRP-alpha homologues, SIRP-beta and -gamma also have synaptic vesicle clustering activity. The effects of SIRP-alpha are distinct from those of another presynaptic organizer, FGF22: the two proteins induced vesicle clusters of different sizes, differed in their ability to promote neurite branching, and acted through different receptors and signaling pathways. SIRP family proteins may act together with other organizing molecules to pattern synapses.     

Catenins: playing both sides of the synapse

Synapses of the central nervous system (CNS) are specialized cell-cell junctions that mediate intercellular signal transmission from one neuron to another. The directional nature of signal relay requires synaptic contacts to be morphologically asymmetric with distinct protein components, while changes in synaptic communication during neural network formation require synapses to be plastic. Synapse morphology and plasticity require a dynamic actin cytoskeleton. Classical cadherins, which are junctional proteins associated with the actin cytoskeleton, localize to synapses and regulate synaptic adhesion, stability and remodeling. The major intracellular components of cadherin junctions are the catenin proteins, and increasing evidence suggests that cadherin-catenin complexes modulate an array of synaptic processes. Here we review the role of catenins in regulating the development of pre- and postsynaptic compartments and function in synaptic plasticity, with particular focus on their role in regulating the actin cytoskeleton.     

Pro-BDNF–induced synaptic depression and retraction at developing neuromuscular synapses

Postsynaptic cells generate positive and negative signals that retrogradely modulate presynaptic function. At developing neuromuscular synapses, prolonged stimulation of muscle cells induces sustained synaptic depression. We provide evidence that pro–brain-derived neurotrophic factor (BDNF) is a negative retrograde signal that can be converted into a positive signal by metalloproteases at the synaptic junctions. Application of pro-BDNF induces a dramatic decrease in synaptic efficacy followed by a retraction of presynaptic terminals, and these effects are mediated by presynaptic pan-neurotrophin receptor p75 (p75^NTR), the pro-BDNF receptor. A brief stimulation of myocytes expressing cleavable or uncleavable pro-BDNF elicits synaptic potentiation or depression, respectively. Extracellular application of metalloprotease inhibitors, which inhibits the cleavage of endogenous pro-BDNF, facilitates the muscle stimulation–induced synaptic depression. Inhibition of presynaptic p75^NTR or postsynaptic BDNF expression also blocks the activity-dependent synaptic depression and retraction. These results support a model in which postsynaptic secretion of a single molecule, pro-BDNF, may stabilize or eliminate presynaptic terminals depending on its proteolytic conversion at the synapses.