A mathematical model of the tripartite synapse: astrocyte-induced synaptic plasticity

In this paper, we present a biologically detailed mathematical model of tripartite synapses, where astrocytes modulate short-term synaptic plasticity. The model consists of a pre-synaptic bouton, a post-synaptic dendritic spine-head, a synaptic cleft and a peri-synaptic astrocyte controlling Ca^2 + dynamics inside the synaptic bouton. This in turn controls glutamate release dynamics in the cleft. As a consequence of this, glutamate concentration in the cleft has been modeled, in which glutamate reuptake by astrocytes has also been incorporated. Finally, dendritic spine-head dynamics has been modeled. As an application, this model clearly shows synaptic potentiation in the hippocampal region, i.e., astrocyte Ca^2 + mediates synaptic plasticity, which is in conformity with the majority of the recent findings (Perea and Araque (Science 317, 1083–1086, 2007); Henneberger et al. (Nature 463, 232–236, 2010); Navarrete et al. (PLoS Biol. 10, e1001259, 2012)).

Electronic supplementary material

The online version of this article (doi:10.1007/s10867-012-9267-7) contains supplementary material, which is available to authorized users.     

Ion dynamics at the energy-deprived tripartite synapse

The anatomical and functional organization of neurons and astrocytes at ‘tripartite synapses’ is essential for reliable neurotransmission, which critically depends on ATP. In low energy conditions, synaptic transmission fails, accompanied by a breakdown of ion gradients, changes in membrane potentials and cell swelling. The resulting cellular damage and cell death are causal to the often devastating consequences of an ischemic stroke. The severity of ischemic damage depends on the age and the brain region in which a stroke occurs, but the reasons for this differential vulnerability are far from understood. In the present study, we address this question by developing a comprehensive biophysical model of a glutamatergic synapse to identify key determinants of synaptic failure during energy deprivation. Our model is based on fundamental biophysical principles, includes dynamics of the most relevant ions, i.e., Na⁺, K⁺, Ca²⁺, Cl⁻ and glutamate, and is calibrated with experimental data. It confirms the critical role of the Na⁺/K⁺-ATPase in maintaining ion gradients, membrane potentials and cell volumes. Our simulations demonstrate that the system exhibits two stable states, one physiological and one pathological. During energy deprivation, the physiological state may disappear, forcing a transit to the pathological state, which can be reverted when blocking voltage-gated Na⁺ and K⁺ channels. Our model predicts that the transition to the pathological state is favoured if the extracellular space fraction is small. A reduction in the extracellular space volume fraction, as, e.g. observed with ageing, will thus promote the brain’s susceptibility to ischemic damage. Our work provides new insights into the brain’s ability to recover from energy deprivation, with translational relevance for diagnosis and treatment of ischemic strokes.     

Syntaxin-1通过激活突触递质传递加速早期突触的形成

Syntaxin-1是一种多结构域蛋白,通过与synaptobrevin-2和SNAP-25形成SNARE复合体调节囊泡融合.然而,syntaxin-1在突触形成过程中是否发挥作用,目前尚不清楚.本研究显示syntaxin-1的表达水平与突触形成过程高度相关.Syntaxin-1的R151A和I155A突变影响其在突触形成中的促进作用,而Habc结构域或跨膜结构域在突触形成中无显著作用.结果表明,syntaxin-1通过激活突触囊泡释放来加速突触的形成.     

A tripartite synapse model in Drosophila

Tripartite (three-part) synapses are defined by physical and functional interactions of glia with pre- and post-synaptic elements. Although tripartite synapses are thought to be of widespread importance in neurological health and disease, we are only beginning to develop an understanding of glial contributions to synaptic function. In contrast to studies of neuronal mechanisms, a significant limitation has been the lack of an invertebrate genetic model system in which conserved mechanisms of tripartite synapse function may be examined through large-scale application of forward genetics and genome-wide genetic tools. Here we report a Drosophila tripartite synapse model which exhibits morphological and functional properties similar to those of mammalian synapses, including glial regulation of extracellular glutamate, synaptically-induced glial calcium transients and glial coupling of synapses with tracheal structures mediating gas exchange. In combination with classical and cell-type specific genetic approaches in Drosophila, this model is expected to provide new insights into the molecular and cellular mechanisms of tripartite synapse function.     

Spillover of glutamate onto synaptic AMPA receptors enhances fast transmission at a cerebellar synapse

Diffusion of glutamate from the synaptic cleft can activate high-affinity receptors, but is not thought to contribute to fast AMPA receptor-mediated transmission. Here, we show that single AMPA receptor EPSCs at the cerebellar mossy fiber-granule cell connection are mediated by both direct release of glutamate and rapid diffusion of glutamate from neighboring synapses. Immunogold localization revealed that AMPA receptors are located exclusively in postsynaptic densities, indicating that spillover of glutamate occurs between synaptic contacts. Spillover currents contributed half the synaptic charge and exhibited little trial-to-trial variability. We propose that spillover of glutamate improves transmission efficacy by both increasing the amplitude and duration of the EPSP and reducing fluctuations arising from the probabilistic nature of transmitter release.     

Roles of SNARE proteins and synaptotagmin I in synaptic transmission: studies at the Drosophila neuromuscular synapse

The roles of SNARE proteins, i.e. neuronal Synaptobrevin (n-Syb), SNAP-25 and Syntaxin 1A (Syx 1A), and Synaptotagmin I (Syt I) in synaptic transmission have been studied in situ using mutant embryos or larvae that lack these molecules or have alterations in them. Because of the ease of genetic manipulation, the Drosophila neuromuscular synapse is widely used for these studies. The functional properties of synaptic transmission have been studied in mutant embryos using the patch-clamp technique, and in larvae by recording with microelectrodes. A major vesicular membrane protein, n-Syb, is indispensable for nerve-evoked synaptic transmission. Spontaneous synaptic currents (minis), however, are present even in embryos totally lacking n-Syb (N-SYB). Furthermore, Ca(2+)-independent enhancement of mini frequency induced by hypertonic sucrose solutions (hypertonicity response) is totally absent in N-SYB. Embryos that have defects in SNAP-25 (SNAP-25) have similar but milder phenotypes than N-SYB. The phenotype in synaptic transmission was most severe in the synapse lacking Syx 1A. Neither nerve-evoked synaptic currents nor minis occur in embryos lacking Syx 1A (SYX 1A). No hypertonicity response was observed in them. Syt I binds Ca(2+) in vitro and probably serves as a Ca(2+) sensor for nerve-evoked synaptic transmission, since nerve-evoked synaptic currents were greatly reduced in embryos lacking Syt I (SYT I). Also, Syt I has a role in vesicle recycling. Interestingly, the Ca(2+)-independent hypertonicity response is also greatly reduced in SYT I. Minis persist in mutant embryos lacking any of these proteins (n-Syb, SNAP-25 and Syt I), except Syx, suggesting that minis have a distinct fusion mechanism from that for fast and synchronized release. It appears that these SNARE proteins and Syt I are coordinated for fast vesicle fusion. Minis, on the other hand, do not require SNARE complex nor Syt I, but Syx is absolutely required for vesicle fusion. The SNARE complex and Syt I are indispensable for the hypertonicity response. None of these molecules seem to serve for selective docking of synaptic vesicles to the release site. For further studies on synaptic transmission, the Drosophila neuromuscular synapse will continue to be a useful model.     

The tripartite synapse: roles for gliotransmission in health and disease

In addition to being essential supporters of neuronal function, astrocytes are now recognized as active elements in the brain. Astrocytes sense and integrate synaptic activity and, depending on intracellular Ca(2+) levels, release gliotransmitters (e.g. glutamate, d-serine and ATP) that have feedback actions on neurons. Recent experimental results have raised the possibility that quantitative variations in gliotransmission might contribute to disorders of the nervous system. Here, we discuss targeted molecular genetic approaches that have demonstrated that alterations in protein expression in astrocytes can lead to serious changes in neuronal function. We also introduce the concept of 'astrocyte activation spectrum' in which enhanced and reduced gliotransmission might contribute to epilepsy and schizophrenia, respectively. The results of future experimental tests of the astrocyte activation spectrum, which relates gliotransmission to neurological and psychiatric disorders, might point to a new therapeutic target in the brain.     

Modeling activity-dependent synapse restructuring

The spread of electrical activity in a dendritic tree is shaped, in part, by its morphology. Conversely, experimental evidence is growing that electrical and chemical activity can slowly shape the morphology of the dendrite. In this theoretical study, the dendritic spines are dynamic elements, with biophysical properties that change in response to patterns of electrical activity. Recent experiments and diagrammatic models suggest that activity-dependent processes can regulate structural modifications in dendritic spines as well as their distribution along the dendrite. This study considers how local changes in spine structure (minutes to hours) can influence patterns of electrical activity along the dendrite; and how electrical activity due to synaptic events and excitable membrane dynamics can, over time, influence the morphology of the dendrite. The model presents a slow subsystem for structural synaptic plasticity associated with long-term potentiation. A perturbation problem evolves naturally when the spine stem shortens, since the ratio of spine stem resistance to input resistance is small. Hence, the difference between the spine head and dendritic potentials become negligible. This paper presents an asymptotic expansion of head potential in terms of dendritic potential. This leads to a reduced model for post-synaptic restructuring that captures the dynamics of the full model in a briefer computation period when the spines are well connected to the dendrite.     

Greasing transmission: palmitoylation at the synapse

Posttranslational modifications such as palmitoylation have the ability to modulate protein localization and function. The reversible addition of the fatty acid palmitate to proteins has been known to occur in neurons for a considerable amount of time and has been noticed to be of particular importance at synapses. In this issue of Neuron, Huang et al. and Fukata et al. describe their studies of palmitoyl transferases and how these enzymes specifically catalyze the modification of a number of synaptic proteins, including the postsynaptic scaffolding protein PSD-95.     

The effects of ethanol on pre-synaptic components of synaptic transmission in a model glutamatergic synapse: the crayfish neuromuscular junction

We have elucidated some of the mechanisms by which ethanol (EtOH) reduces synaptic efficacy at model glutamatergic synapses. The crayfish phasic and tonic neuromuscular junctions are superb models for directly assessing the effects of EtOH on pre-synaptic components of synaptic transmission. The ability to perform quantal analysis of synaptic transmission has allowed us to assess pre-synaptic alterations of release. Using this system, we report that the application of EtOH, within a range observed in intoxicated humans (44 and 88 mM), resulted in a diminution of excitatory post-synaptic potentials (EPSP) amplitudes. Additionally, using focal macro-patch recordings, quantal synaptic currents were recorded to assess the pre-synaptic component as potential target sites for EtOH's action. At the tonic neuromuscular junctions, EtOH (88 mM) reduced the probability of release (p), and in some cases, reduced the number of the release sites (n), but did not alter facilitation index nor did it affect the latency of vesicular release. At the phasic neuromuscular junction, a reduction in synaptic charge occurred during the presence of EtOH. Thus, the observed decrease in synaptic strength is at least partially attributable to a pre-synaptic alteration, specifically the release of fewer vesicles.     

Long-lasting synaptic potentials and the modulation of synaptic transmission.

Long-lasting postsynaptic potentials (PSPs) generated by decreases in membrane conductance (permeability) have been reported in many types of neurons. We investigated the possible role of such long-lasting decreases in membrane conductance in the modulation of synaptic transmission in the sympathetic ganglion of the bullfrog. The molecular basis by which such conductance-decrease PSPs are generated was also investigated. Synaptic activation of muscarinic cholinergic receptors on these sympathetic neurons results in the generation of a slow EPSP (excitatory postsynaptic potential), which is accompanied by a decrease in membrane conductance. We found that the conventional "fast" EPSPs were increased in amplitude and duration during the iontophoretic application of methacholine, which activates the muscarinic postsynaptic receptors. A similar result was obtained when a noncholinergic conductance-decrease PSP--the late-slow EPSP--was elicited by stimulation of a separate synaptic pathway. The enhancement of fast EPSP amplitude increased the probability of postsynaptic action potential generation, thus increasing the efficacy of impulse transmission across the synapse. Stimulation of one synaptic pathway is therefore capable of increasing the efficacy of synaptic transmission in a second synaptic pathway by a postsynaptic mechanism. Furthermore, this enhancement of synaptic efficacy is long-lasting by virtue of the long duration of the slow PSP. Biochemical and electrophysiological techniques were used to investigate whether cyclic nucleotides are intracellular second messengers mediating the membrane permeability changes underlying slow-PSP generation. Stimulation of the synaptic inputs, which lead to the generation of the slow-PSPs, increased the ganglionic content of both cyclic AMP and cyclic GMP. However, electrophysiological analysis of the actions of these cyclic nucleotides and the actions of agents that affect their metabolism does not provide support for such a second messenger role for either cyclic nucleotide.     

Role of the synaptic microenvironment in functional modification of synaptic transmission

Experiments on hippocampal slices showed that perfusion with a dextran solution more effectively facilitates AMPA-mediated transmission in structurally complex synapses of mossy fibers of Shaffer collaterals. Estimates for changes in the extracellular Ca²⁺ concentration in the close vicinity of a reconstructed synapse during the action potential development are obtained. The results together with data about the rather small (0.5 μm) characteristics distance between neighboring synapses showed that the probability of mutual intersynaptic influence via the microenvironment is high. A probable functional role of such influences is discussed.     

Sunrise at the synapse: the FMRP mRNP shaping the synaptic interface

Recent studies provide new insight into the mechanistic function of Fragile X Mental Retardation Protein (FMRP), paving the way to understanding the biological basis of Fragile X Syndrome. While it has been known for several years that there are spine defects associated with the absence of the mRNA binding protein FMRP, it has been unclear how its absence may lead to specific synaptic defects that underlie the learning and cognitive impairments in Fragile X. One hypothesis under study is that FMRP may play a key role in the regulation of dendritically localized mRNAs, at subsynaptic sites where regulation of local protein synthesis may influence synaptic structure and plasticity. This review highlights recent progress to identify the specific mRNA targets of FMRP and assess defects in mRNA regulation that occur in cells lacking FMRP. In addition, exciting new studies on Fmr1 knockout mice and mutant flies have begun to elucidate a key role for FMRP in synaptic growth, structure, and long-term plasticity.     

LAR-RPTPs: synaptic adhesion molecules that shape synapse development

The synapse is the most elementary operating unit in neurons, creating neural circuits that underlie all brain functions. Synaptic adhesion molecules initiate neuronal synapse connections, promote their stabilization and refinement, and control long-term synaptic plasticity. Leukocyte common antigen-related receptor protein tyrosine phosphatases (LAR-RPTPs) have previously been implicated as essential elements in central nervous system (CNS) development. Recent studies have demonstrated that LAR-RPTP family members are also involved in diverse synaptic functions, playing a role in synaptic adhesion pathways together with a host of distinct transmembrane proteins and serving as major synaptic adhesion molecules in governing pre- and postsynaptic development, dysfunctions of which may underlie various disorders. This review highlights the emerging role of LAR-RPTPs as synapse organizers in orchestrating synapse development.