The Influence of Synaptic Size on AMPA Receptor Activation: A Monte Carlo Model

Physiological and electron microscope studies have shown that synapses are functionally and morphologically heterogeneous and that variations in size of synaptic junctions are related to characteristics such as release probability and density of postsynaptic AMPA receptors. The present article focuses on how these morphological variations impact synaptic transmission. We based our study on Monte Carlo computational simulations of simplified model synapses whose morphological features have been extracted from hundreds of actual synaptic junctions reconstructed by three-dimensional electron microscopy. We have examined the effects that parameters such as synaptic size or density of AMPA receptors have on the number of receptors that open after release of a single synaptic vesicle. Our results indicate that the maximum number of receptors that will open after the release of a single synaptic vesicle may show a ten-fold variation in the whole population of synapses. When individual synapses are considered, there is also a stochastical variability that is maximal in small synapses with low numbers of receptors. The number of postsynaptic receptors and the size of the synaptic junction are the most influential parameters, while the packing density of receptors or the concentration of extrasynaptic transporters have little or no influence on the opening of AMPA receptors.     

Redistribution of synaptic efficacy: A mechanism to generate infinite synaptic input diversity from a homogenous population of neurons without changing absolute synaptic efficacies

Changing the reliability of neurotransmitter release results in a change in the efficay of low frequency synaptic transmission and in the rate of high frequency synaptic depression thus it can not cause an uniform change in strength of synapses and instead results in a change in the dynamics of synaptic transmission referred to as ‘redistribution of synaptic efficacy’ (RSE). Since the change in synaptic transmission associated with RSE depends on the history of action potential activity it is concluded that RSE serves as a mechanism to generate a potentially infinite diversity of synaptic input.     

Astrocytes in endocannabinoid signalling

Astrocytes are emerging as integral functional components of synapses, responding to synaptically released neurotransmitters and regulating synaptic transmission and plasticity. Thus, they functionally interact with neurons establishing tripartite synapses: a functional concept that refers to the existence of communication between astrocytes and neurons and its crucial role in synaptic function. Here, we discuss recent evidence showing that astrocytes are involved in the endocannabinoid (ECB) system, responding to exogenous cannabinoids as well as ECBs through activation of type 1 cannabinoid receptors, which increase intracellular calcium and stimulate the release of glutamate that modulates synaptic transmission and plasticity. We also discuss the consequences of ECB signalling in tripartite synapses on the astrocyte-mediated regulation of synaptic function, which reveal novel properties of synaptic regulation by ECBs, such as the spatially controlled dual effect on synaptic strength and the lateral potentiation of synaptic efficacy. Finally, we discuss the potential implications of ECB signalling for astrocytes in brain pathology and animal behaviour.     

Dynamic action of neurometals at the synapse

There are synaptic vesicles that are labeled by Timm's sulfide-silver staining method in the brain, suggesting that synaptic vesicles contain metals such as zinc and copper. Zinc is co-released with glutamate and the importance of zinc signaling in the intracellular compartment, in addition to extracellular compartment, is becoming recognized. Zinc can pass through calcium channels, while blocking them. Calcium signaling plays a critical role for synaptic activity and crosstalk between zinc signaling with calcium signaling through calcium channels may participate in synaptic neurotransmission including synaptic plasticity such as long-term potentiation. Copper released into the synaptic cleft during synaptic excitation may also participate in synaptic neurotransmission. Other metals including copper potentially serve as calcium channel blockers and also influence calcium signaling and zinc signaling via the interaction with metal-binding proteins such as metallothioneins. Homeostasis of metals needs to be controlled spatiotemporally for proper brain function, and their dyshomeostasis is associated with neurological diseases. However, the data on the dynamic action of metals at synapses is limited and their significance poorly understood. This paper summarizes the action of metals in synaptic neurotransmission focused on calcium signaling at glutamatergic synapses.     

Voltage-gated calcium channels

Voltage-gated calcium (Ca(2+)) channels are key transducers of membrane potential changes into intracellular Ca(2+) transients that initiate many physiological events. There are ten members of the voltage-gated Ca(2+) channel family in mammals, and they serve distinct roles in cellular signal transduction. The Ca(V)1 subfamily initiates contraction, secretion, regulation of gene expression, integration of synaptic input in neurons, and synaptic transmission at ribbon synapses in specialized sensory cells. The Ca(V)2 subfamily is primarily responsible for initiation of synaptic transmission at fast synapses. The Ca(V)3 subfamily is important for repetitive firing of action potentials in rhythmically firing cells such as cardiac myocytes and thalamic neurons. This article presents the molecular relationships and physiological functions of these Ca(2+) channel proteins and provides information on their molecular, genetic, physiological, and pharmacological properties.     

Endocytosis at ribbon synapses

Unlike conventional synaptic terminals that release neurotransmitter episodically in response to action potentials, neurons of the visual, auditory and vestibular systems encode sensory information in graded signals that are transmitted at their synapses by modulating the rate of continuous release. The synaptic ribbon, a specialized structure found at the active zones of these neurons, is necessary to sustain the high rates of exocytosis required for continuous release. To maintain the fidelity of synaptic transmission, exocytosis must be balanced by high-capacity endocytosis, to retrieve excess membrane inserted during vesicle fusion. Capacitance measurements following vesicle release in ribbon-type neurons indicate two kinetically distinct phases of compensatory endocytosis, whose relative contributions vary with stimulus intensity. The two phases can be independently regulated and may reflect different underlying mechanisms operating on separate pools of recycling vesicles. Electron microscopy shows diversity among ribbon-type synapses in the relative importance of clathrin-mediated endocytosis versus bulk membrane retrieval as mechanisms of compensatory endocytosis. Ribbon synapses, like conventional synapses, make use of multiple endocytosis pathways to replenish synaptic vesicle pools, depending on the physiological needs of the particular cell type.     

Population rate coding in recurrent neuronal networks with unreliable synapses

Neuron transmits spikes to postsynaptic neurons through synapses. Experimental observations indicated that the communication between neurons is unreliable. However most modelling and computational studies considered deterministic synaptic interaction model. In this paper, we investigate the population rate coding in an all-to-all coupled recurrent neuronal network consisting of both excitatory and inhibitory neurons connected with unreliable synapses. We use a stochastic on-off process to model the unreliable synaptic transmission. We find that synapses with suitable successful transmission probability can enhance the encoding performance in the case of weak noise; while in the case of strong noise, the synaptic interactions reduce the encoding performance. We also show that several important synaptic parameters, such as the excitatory synaptic strength, the relative strength of inhibitory and excitatory synapses, as well as the synaptic time constant, have significant effects on the performance of the population rate coding. Further simulations indicate that the encoding dynamics of our considered network cannot be simply determined by the average amount of received neurotransmitter for each neuron in a time instant. Moreover, we compare our results with those obtained in the corresponding random neuronal networks. Our numerical results demonstrate that the network randomness has the similar qualitative effect as the synaptic unreliability but not completely equivalent in quantity.     

Effect of cytochalasin D on the structure of mixed synapses and their electrotonic conductivity]

By methods of qualitative and quantitative electronmicroscopy the ultrastructure of mixed synapses of the goldfish Mauthner cell (MC) and their ability to strengthen electrotonic transmission after application of cytochalasin D, a highly specific inhibitor of actin polymerization. On the background of cytochalasin action tetranization of afferent rootlets of acoustic nerve, terminated with mixed synapses on the MC lateral dendrite, failed to induce any long-term potentiation of electronic coupling. On the contrary, a long-term depression of electrotonic transmission was evoked in this case. On the ultrastructureal level such a depression of synaptic conductivity was seen to correlate with a decrease in the number and total length per synaptic apposition of the desmosome-like contacts, known as actin-containing structures, as compared with unstimulated control preparations. In addition, experimental preparations were characterized with unusual quantity of asymmetric desmosome-like contacts, hemidesmosome, whose number during a long-term depression became 4 fold higher than in the control synapses. The data obtained support our recent suggestion on the role of filamentous actin in induction and long-term maintenance of enhanced electrotonic conductivity at mixed synapses.     

Synaptic cell adhesion

Chemical synapses are asymmetric intercellular junctions that mediate synaptic transmission. Synaptic junctions are organized by trans-synaptic cell adhesion molecules bridging the synaptic cleft. Synaptic cell adhesion molecules not only connect pre- and postsynaptic compartments, but also mediate trans-synaptic recognition and signaling processes that are essential for the establishment, specification, and plasticity of synapses. A growing number of synaptic cell adhesion molecules that include neurexins and neuroligins, Ig-domain proteins such as SynCAMs, receptor phosphotyrosine kinases and phosphatases, and several leucine-rich repeat proteins have been identified. These synaptic cell adhesion molecules use characteristic extracellular domains to perform complementary roles in organizing synaptic junctions that are only now being revealed. The importance of synaptic cell adhesion molecules for brain function is highlighted by recent findings implicating several such molecules, notably neurexins and neuroligins, in schizophrenia and autism.     

Role of the adenylate cyclase system in cholinergic modulation of synaptic transmission in the hippocampus

Involvement of the adenylate cyclase system in cholinergic modulation of synaptic transmission was investigated in area CA1 in rat hippocampal slices. Microiontophoretic application of acetylcholine as well as addition of carbachol to the superfusate or of tolbutamide (a cAMP-dependent protein kinase inhibitor) depressed transmission at synapses formed by Schaffer collaterals and commissural fibers with dendrites of pyramidal cells belonging to hippocampal area CA1. Both numbers of free quanta of neurotransmitter and the likelihood of transmitter release decreased following carbachol action. Atropine suppressed the inhibitory action of carbachol on synaptic transmission. Dibutyryl cAMP and forskolin increased the amplitude of synaptic potentials and suppressed, either partially or in full, the inhibitory effects of cholinomimetics on synaptic potentials. It was concluded that cholinomimetics and activators of the adenylate cyclase system exert opposing effects on neurotransmission at synapses formed between Schaffer collaterals/commissural fibers and dendrites of pyramidal neurons belonging to hippocampal area CA1.Institute of Biophysics, Academy of Sciences of the USSR, Pushchino. Translated from Neirofiziologiya, Vol. 21, No. 4, pp. 435–442, July–August, 1989.     

Maintained depolarization of synaptic terminals facilitates nerve-evoked transmitter release at a crayfish neuromuscular junction

Presynaptic and postsynaptic potentials were examined by intracellular recording at a crayfish neuromuscular junction. During normal synaptic transmission, the action potentials were recorded in the terminal region of the excitatory axon and postsynaptic responses were obtained in the muscle fibers. We found that it was possible to modify the synaptic transmission by applying depolarizing or hyperpolarizing currents through the presynaptic intracellular electrode. Typically, a 7-15 mV depolarization lasting longer than 50 msec leads to a large (500%) enhancement of transmitter release, even though the preterminal action potential is reduced in amplitude. Hyperpolarization increases the amplitude of the action potential, but slightly reduces the transmitter release. These results are different from those reported for other neuromuscular synapses and the squid giant synapse, but are similar in many respects to the results reported for several invertebrate central synapses. We conclude, first, that different synapses may have markedly different responses to conditioning by membrane polarization and, secondly, that maintained low-level depolarization may induce a potentiated state in the nerve terminal, perhaps brought about by slow entry of calcium.     

Astrocytes are endogenous regulators of basal transmission at central synapses

Basal synaptic transmission involves the release of neurotransmitters at individual synapses in response to a single action potential. Recent discoveries show that astrocytes modulate the activity of neuronal networks upon sustained and intense synaptic activity. However, their ability to regulate basal synaptic transmission remains ill defined and controversial. Here, we show that astrocytes in the hippocampal CA1 region detect synaptic activity induced by single-synaptic stimulation. Astrocyte activation occurs at functional compartments found along astrocytic processes and involves metabotropic glutamate subtype 5 receptors. In response, astrocytes increase basal synaptic transmission, as revealed by the blockade of their activity with a Ca(2+) chelator. Astrocytic modulation of basal synaptic transmission is mediated by the release of purines and the activation of presynaptic A(2A) receptors by adenosine. Our work uncovers an essential role for astrocytes in the regulation of elementary synaptic communication and provides insight into fundamental aspects of brain function.     

Synaptic transmission is impaired at neuronal autonomic synapses in agrin-null mice

Neuronal synapse formation is a multistep process regulated by several pre- and postsynaptic adhesion and signaling proteins. Recently, we found that agrin acts as one such synaptogenic factor at neuronal synapses in the PNS by demonstrating that structural synapse formation is impaired in the superior cervical ganglia (SCG) of z+ agrin-deficient mice and in SCG cultures derived from those animals. Here, we tested whether synaptic function is defective in agrin-null (AGD-/-) ganglia and began to define agrin's mechanism of action. Our electrophysiological recordings of compound action potentials showed that presynaptic stimulation evoked action potentials in approximately 40% of AGD-/- ganglionic neurons compared to 90% of wild-type neurons; moreover, transmission could not be potentiated as in wild-type or z+ agrin-deficient ganglia. Intracellular recordings also showed that nerve-evoked excitatory postsynaptic potentials in AGD-/- neurons were only 1/3 the size of those in wild-type neurons and mostly subthreshold. Consistent with these defects in transmission, we found an approximately 40-50% decrease in synapse number in AGD-/- ganglia and cultures, and decreased levels of differentiation at the residual synapses in culture. Furthermore, surface levels of acetylcholine receptors (AChRs) were equivalent in cultured AGD-/- and wild-type neurons, and depolarization reduced the synaptic localization of AChRs in AGD-/- but not wild-type neurons. These findings provide the first direct demonstration that agrin is required for proper structural and functional development of an interneuronal synapse in vivo. Moreover, they suggest a novel role for agrin, in stabilizing the postsynaptic density of nAChR at nascent neuronal synapses.     

Signaling through Gs alpha is required for the growth and function of neuromuscular synapses in Drosophila

Although synapses are assembled in a highly regulated fashion, synapses once formed are not static structures but continue to expand and retract throughout the life of an organism. One second messenger that has been demonstrated to play a critical role in synaptic growth and function is cAMP. Here, we have tested the idea that signaling through the heterotrimeric G protein, Gs, plays a coincident role with increases in intracellular Ca(+2) in the regulation of adenylyl cyclases (ACs) during synaptic growth and in the function of synapses. In larvae containing a hypomorphic mutation in the dgs gene encoding the Drosophila Gs alpha protein, there is a significant decrease in the number of synaptic boutons and extent of synaptic arborization, as well as defects in the facilitation of synaptic transmission. Microscopic analysis confirmed that Gs alpha is localized at synapses both pre- and postsynaptically. Restricted expression of wild-type Gs alpha either pre- or postsynaptically rescued the mutational defects in bouton formation and defects in the facilitation of synaptic transmission, indicating that pathways activated by Gs alpha are likely to be involved in the reciprocal interactions between pre- and postsynaptic cells required for the development of mature synapses. In addition, this Gs alpha mutation interacted with fasII, dnc, and hyperexcitability mutants in a manner that revealed a coincident role for Gs alpha in the regulation of cAMP and FASII levels required during growth of these synapses. Our results demonstrate that Gs alpha-dependent signaling plays a role in the dynamic cellular reorganization that underlies synaptic growth.     

Analysis and implications of equivalent uniform approximations of nonuniform unitary synaptic systems

Real synaptic systems consist of a nonuniform population of synapses with a broad spectrum of probability and response distributions varying between synapses, and broad amplitude distributions of postsynaptic unitary responses within a given synapse. A common approach to such systems has been to assume identical synapses and recover apparent quantal parameters by deconvolution procedures from measured evoked (ePSC) and unitary evoked postsynaptic current (uePSC) distributions. Here we explicitly consider nonuniform synaptic systems with both intra (type I) and intersynaptic (type II) response variability and formally define an equivalent system of uniform synapses in which both uePSC and ePSC amplitude distributions best approximate those of the actual nonuniform synaptic system. This equivalent system has the advantage of being fully defined by just four quantal parameters: ?, the number of equivalent synapses;p, the mean probability of quantal release; mu, mean; and sigma(2), variance of the uePSC distribution. We show that these equivalent parameters are weighted averages of intrinsic parameters and can be approximated by apparent quantal parameters, therefore establishing a useful analytical link between the apparent and intrinsic parameters. The present study extends previous work on compound binomial analysis of synaptic transmission by highlighting the importance of the product of p and mu, and the variance of that product. Conditions for a unique deconvolution of apparent uniform synaptic parameters have been derived and justified. Our approach does not require independence of synaptic parameters, such as p and mu from each other, therefore the approach will hold even if feedback (i.e., via retrograde transmission) exists between pre and postsynaptic signals. Using numerical simulations we demonstrate how equivalent parameters are meaningful even when there is considerable variation in intrinsic parameters, including systems where subpopulations of high- and low-release probability synapses are present, therefore even under such conditions the apparent parameters estimated from experiments would be informative.     

Effects of ethimizol on frog neuromuscular junction

The effects were studied of ethimizol, a substance activating memory processes, on features of synaptic transmission during experiments on frog cutaneous pectoris muscle. It was found that the presynaptic action of ethimizol consists of raising the frequency of miniature potentials, when used at a concentration of 0.5–10 mM, and modulating quantal content of synaptic transmission due to changes in binomial quantal release parameters p and n when 0.5–2 mM ethimizol was used. This substance facilitated transmission at synapses with a low initial level of transmitter release. This substance facilitated transmission at synapses with a low initial level of transmitter release. Ethimizol was also found to have a postsynaptic action, consisting of reducing amplitude at a concentration of 5–10 mM and prolonging synaptic currents and potentials when concentrations of 0.5–10 mM were used. The latter effect produced a considerable increase in the time integral of endplate potentials. The postsynaptic action of ethimizol is perhaps seen in its effects on features of postsynaptic ionic channels. The effects of ethimizol are discussed with a view to how it may act within the central nervous system as a nonspecific modulator.A. A. Zhdanov Leningrad State University. Translated from Neirofiziologiya, Vol. 17, No. 6, pp. 757–763, November–December, 1985.     

The functional organization and motor innervation of the cervical skeletal muscle in mammals

Structural and functional studies have been done on the nerve-muscle transmission in m. biventer cervicis of mouse using electrophysiological, mechanographic and microscopic techniques. It was shown that each muscle fiber has several synaptic inputs, although m. biventer cervicis is a typical phasic skeletal muscle. Usually, there is a single large synapse of the end-plate type and several small synaptic contacts. Some of the synapses investigated produce typical end-plate potential which is transformed into the action potential. Certain part of synapses are capable of producing action potentials only during facilitation of the transmission by rhythmic stimulation. In curarized preparations, supramaximum single indirect stimulus may evoke in a single point of a fiber multicomponent postsynaptic responses of various amplitude and, sometimes, of various latency. Contractile response of a single segment to a maximum direct stimulation is always higher than to an indirect one. Unusual functional properties of m. biventer cervicis are discussed in relation to peculiarities of its origin.     

A developmental switch in neurotransmitter flux enhances synaptic efficacy by affecting AMPA receptor activation

Formation of glutamatergic synapses entails development of "silent" immature contacts into mature functional synapses. To determine how this transformation occurs, we investigated the development of neurotransmission at single synapses in vitro. Maturation of presynaptic function, assayed with endocytotic markers, followed accumulation of synapsin I. During this period, synaptic transmission was primarily mediated by activation of NMDA receptors, suggesting that most synapses were functionally silent. However, local glutamate application to silent synapses indicated that these synapses contained functional AMPA receptors, suggesting a possible presynaptic locus for silent transmission. Interference with presynaptic vesicle fusion by exposure to tetanus toxin reverted functional to silent transmission, implicating SNARE-mediated fusion as a determinant of the ratio of NMDA:AMPA receptor activation. This work reveals that functional maturation of synaptic transmission involves transformation of presynaptic silent secretion into mature synaptic transmitter release.     

Calcium stores and synaptic plasticity

Chemical transmission at central synapses is known to be highly plastic; the strength of synaptic connections can be modified bi-directionally as a result of activity at individual synapses. Long-term changes in synaptic efficacy, both increases and decreases, are thought to be involved in the development of the nervous system, and in ongoing changes in response to external cues such as during learning and addiction. Other, shorter lasting changes in synaptic transmission are also likely to be important in normal functioning of the CNS. Calcium mobilisation is an important step in multiple forms of plasticity and, although entry into neurones from the extracellular space is often the initial trigger for plasticity changes, release of calcium from intracellular stores also has an important part to play in a variety of forms of synaptic plasticity.