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Methods. A: schematic diagram of a hippocampal slice showing the classical 3-synaptic pathway, the stimulating, and the recording electrodes. Schaffer collateral (Sch) was activated at 0.25 Hz with a pair of stimuli delivered at 50-ms interval (left). Schaffer collateral stimulation evoked in CA1 pyramidal neurons (held at 60 mV)-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-mediated excitatory postsynaptic currents (EPSCs, right). B: schematic representation of a glutamatergic synapse depicted before the first (left) and the second (right) paired stimuli. Each presynaptic vesicle (circle) containing the neurotransmitter (in gray) has a characteristic probability of release p ves. k is the variable representing the number of primed vesicles in the ready releasable pool and q (mean quantal size) is the mean amplitude of the synaptic current obtained by activation of postsynaptic receptors by glutamate released from a single vesicle. C, top: EPSCs evoked by minimal stimulation of Schaffer collateral. Different stimulus intensities were used to evoke synaptic currents in a CA1 pyramidal cell at P3. Each trace is the average of 15-20 responses. Holding potential was 60 mV. Bottom: plot of the peak amplitude of synaptic currents against different stimulus intensities. Note the all-or-none appearance of synaptic currents with increasing stimulus intensities. Error bars indicate SE. Dashed lines connect the mean values of individual points within the same groups. D, left: A 1 and A 2 are the mean amplitude currents elicited by 2 pulses at 50-ms interval; A 2r and A 2f represent the mean amplitude currents to the second pulse given a response or a failure on the first stimulus, respectively. D, right: P 1 and P 2 are the probability of transmitter release after the first or second pulse; P 2r and P 2f are the probability of transmitter release on the second pulse given a response or a failure to the first one, respectively.
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We developed and analytically solved a simple and general stochastic model to distinguish the univesicular from the multivesicular mode of glutamate release. The model solution gives analytical mathematical expressions for average values of quantities that can be measured experimentally. Comparison of these quantities with the experimental measures...
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Context 1
... methiodide (5 M) and tetrodotoxin (TTX, 10 nM) were added to the bath solution to block -aminobutyric acid type A (GABA A ) receptors and reduce polysynaptic activity, respectively. The Schaffer collateral was stimulated with bipolar twisted NiCr- insulated electrodes placed in stratum radiatum. Paired (50-ms, 100-s duration) stimuli (at 0.25 Hz; Fig. 1) were adjusted to evoke minimal EPSCs, which were intermingled with transmission failures. In all analyzed cells, the stimulus intensity was in the range of 3.5-10 V, corresponding to 2.3-6.7 A. According to the technique de- scribed by Jonas et al. (1993) and Allen and Stevens (1994) the stimulation intensity was decreased until only ...
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... scribed by Jonas et al. (1993) and Allen and Stevens (1994) the stimulation intensity was decreased until only a single axon was activated. This was achieved when the mean amplitude of the postsyn- aptic currents and failure probability remained constant over a range of stimulus intensities near threshold for detecting a response. The example of Fig. 1C shows average traces of synaptic currents recorded from a CA1 pyramidal cell in response to different stimulation intensities. An abrupt increase in the mean peak amplitude of synaptic currents was observed when the stimulus intensity was changed from 4.5 to 5 V. The amplitude of responses remained constant for stimu- Schaffer ...
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... a response or a failure to the first one, respectively; the mean quantal size q as the mean amplitude of the synaptic current after the release of a single vesicle; k as the variable counting the number of primed vesicles (i.e., the number of vesicles in the ready releasable pool); and p ves as the probability of release of each single vesicle (Fig. ...
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... Taken together, our data indicate that p syn is very variable between boutons and highly dependent on [Ca 2+ ] e . As p syn increased, so did the reported glutamate concentration, consistent with the capacity of Schaffer collateral boutons for multivesicular release [15][16][17][18][19][20] . ...
Information processing in the brain is controlled by quantal release of neurotransmitters, a tightly regulated process. From ultrastructural analysis, it is known that presynaptic boutons along single axons differ in the number of vesicles docked at the active zone. It is not clear whether the probability of these vesicles to get released (pves) is homogenous or also varies between individual boutons. Here, we optically measure evoked transmitter release at individual Schaffer collateral synapses at different calcium concentrations, using the genetically encoded glutamate sensor iGluSnFR. Fitting a binomial model to measured response amplitude distributions allowed us to extract the quantal parameters N, pves, and q. We find that Schaffer collateral boutons typically release single vesicles under low pves conditions and switch to multivesicular release in high calcium saline. The potency of individual boutons is highly correlated with their vesicular release probability while the number of releasable vesicles affects synaptic output only under high pves conditions.
... Taken together, these data indicate that psyn is very variable between boutons and highly 121 dependent on [Ca 2+ ]e. Furthermore, as psyn increased, so did the cleft glutamate, consistent with 122 the capacity of Schaffer collateral boutons for multivesicular release [14][15][16][17][18][19] . 123 ...
Information processing in the brain is controlled by quantal release of neurotransmitters, a tightly regulated process. Even in a single axon, presynaptic boutons differ in the number of docked vesicles, but it is not known if the vesicular release probability (p ves ) is homogenous or variable between individual boutons. We optically measured evoked transmitter release at individual Schaffer collateral synapses using the genetically encoded glutamate sensor iGluSnFR, localizing the fusion site on the bouton with high spatiotemporal precision. Fitting a binomial model to measured response amplitude distributions allowed us to extract the quantal parameters N, p ves , and q. Schaffer collateral boutons typically released only a single vesicle under low p ves conditions and switched to multivesicular release in high calcium saline. We found that p ves was highly variable between individual boutons and had a dominant impact on presynaptic output.
... Taken together, these data indicate that psyn is very variable between boutons and highly dependent on [Ca 2+ ]e. Furthermore, as psyn increased, so did the cleft glutamate, consistent with the capacity of Schaffer collateral boutons for multivesicular release (Tong and Jahr, 1994;Bolshakov et al., 1997;Oertner et al., 2002;Christie and Jahr, 2006;Ricci-Tersenghi et al., 2006;Boucher et al., 2010). ...
... Although previous studies using postsynaptic measurements of AMPAR currents found evidence for multivesicular release at Schaffer collateral synapses (Tong and Jahr, 1994;Bolshakov et al., 1997;Oertner et al., 2002;Christie and Jahr, 2006;Ricci-Tersenghi et al., 2006;Boucher et al., 2010) and in dissociated hippocampal cultures (Abenavoli et al., 2002;Watanabe et al., 2013), it has not been possible to compare the amplitude of evoked responses to the amplitude of spontaneous fusion events ('minis') at the same synapse. To perform a classical quantal analysis, the size of the quantum (q) has to be known. ...
Information processing in the brain is controlled by quantal release of glutamate, a tightly regulated process. Even in a single axon, presynaptic boutons differ in the number of docked vesicles, but it is not known if the vesicular release probability (pves) is homogenous or variable between individual boutons. We optically measured evoked transmitter release at individual Schaffer collateral synapses using the genetically encoded glutamate sensor iGluSnFR, localizing the fusion site on the bouton with high spatiotemporal precision. Fitting a binomial model to measured response amplitude distributions allowed us to extract the quantal parameters n, pves, and q. Schaffer collateral boutons typically released only a single vesicle under low pves conditions and switched to multivesicular release in high calcium saline. We found that pves was highly variable between individual boutons and had a dominant impact on presynaptic output.
... While there is no existing explanation for such refractoriness, there are several manners in which such lateral inhibition of release following the exocytosis of one of the vesicles could occur (Nadkarni et al., 2010). Nonetheless, evidence for multivesicular release has been presented for a number of synapses, including the CA3-CA1 synapses (Oertner et al., 2002;Christie and Jahr, 2006;Ricci-Tersenghi et al., 2006), and the notion that each docking site is an independent release site is now considered the favored one (Rudolph et al., 2015;Pulido and Marty, 2017). However, even quite small synapses (active zone areas of 0.05-0.1 µm 2 ) may contain more than one nanomodule (Hruska et al., 2018), resulting in multivesicular release but from morphologically separate release regions (nanomodules) within an active zone, assuming that a possible lateral inhibition of release among the vesicles is restricted to vesicles within a nanomodule. ...
Advanced imaging techniques have revealed that synapses contain nanomodules in which pre- and post-synaptic molecules are brought together to form an integrated subsynaptic component for vesicle release and transmitter reception. Based on data from an electrophysiological study of ours in which release from synapses containing a single nanomodule was induced by brief 50 Hz trains using minimal stimulation, and on data from such imaging studies, we present a possible modus operandi of such a nanomodule. We will describe the techniques and tools used to obtain and analyze the electrophysiological data from single CA3–CA1 hippocampal synapses from the neonatal rat brain. This analysis leads to the proposal that a nanomodule, despite containing a number of release locations, operates as a single release site, releasing at most a single vesicle at a time. In this nanomodule there appears to be two separate sets of release locations, one set that is responsible for release in response to the first few action potentials and another set that produces the release thereafter. The data also suggest that vesicles at the first set of release locations are primed by synaptic inactivity lasting seconds, this synaptic inactivity also resulting in a large heterogeneity in the values for vesicle release probability among the synapses. The number of vesicles being primed at this set of release locations prior to the arrival of an action potential is small (0–3) and varies from train to train. Following the first action potential, this heterogeneity in vesicle release probability largely vanishes in a release-independent manner, shaping a variation in paired-pulse plasticity among the synapses. After the first few action potentials release is produced from the second set of release locations, and is given by vesicles that have been recruited after the onset of synaptic activity. This release depends on the number of such release locations and the recruitment to such a location. The initial heterogeneity in vesicle release probability, its disappearance after a single action potential, and variation in the recruitment to the second set of release locations are instrumental in producing the heterogeneity in short-term synaptic plasticity among these synapses, and can be seen as means to create differential dynamics within a synapse population.
... ). Although we cannot distinguish between the release of multiple vesicles from a single release site or the existence of multiple release sites, our interpretation is consistent with the model of multi-quantal CA1 synapses, in which a single action potential may induce the release of more than one vesicle from the same release site(Conti & Lisman, 2003;Ricci-Tersenghi, Minneci, Sola, Cherubini, & Maggi, 2006;Singh, Hockenberry, Tiruvadi, & Meaney, 2011). Thus, the most likely scenario is that CA3-CA1 synapses inCx3cr1 KO have multiple release sites operating at low probability. ...
Deficient neuron–microglia signaling during brain development is associated with abnormal synaptic maturation. However, the precise impact of deficient microglia function on synaptic maturation and the mechanisms involved remain poorly defined. Here we report that mice defective in neuron‐to‐microglia signaling via the fractalkine receptor (Cx3cr1 KO) show reduced microglial branching and altered motility and develop widespread deficits in glutamatergic neurotransmission. We characterized the functional properties of CA3–CA1 synapses in hippocampal slices from these mice and found that they display altered glutamatergic release probability, maintaining immature properties also at late developmental stages. In particular, CA1 synapses of Cx3cr1 KO show (i) immature AMPA/NMDA ratio across developmental time, displaying a normal NMDA component and a defective AMPA component of EPSC; (ii) defective functional connectivity, as demonstrated by reduced current amplitudes in the input/output curve; and (iii) greater facilitation in the paired pulse ratio (PPR), suggesting decreased release probability. In addition, minimal stimulation experiments revealed that excitatory synapses have normal potency, but an increased number of failures, confirming a deficit in presynaptic release. Consistently, KO mice were characterized by higher number of silent synapses in comparison to WT. The presynaptic deficits were corrected by performing experiments in conditions of high release probability (Ca²⁺/Mg²⁺ratio 8), where excitatory synapses showed normal synaptic multiplicity, AMPA/NMDA ratio, and proportion of silent synapses. These results establish that neuron–microglia interactions profoundly influence the functional maturation of excitatory presynaptic function.
... Although initial studies rejected the MVR hypothesis [104,105], considerable variability in postsynaptic currents, as well as in anatomical and molecular properties, led to the speculation that hippocampal synapses use MVR to increase their dynamic range [11,30,83,106] (Box 1 and Figure 2). Indeed, modeling of SC-CA1 EPSCs also favors the idea that MVR underlies current amplitude fluctuations [29,107]. A pioneering study in cultured hippocampal neurons identified MVR based on observations that multiple quanta interact with a common population of postsynaptic receptors [12]. ...
'Simplicity is prerequisite for reliability' (E.W. Dijkstra [1]) Presynaptic action potentials trigger the fusion of vesicles to release neurotransmitter onto postsynaptic neurons. Each release site was originally thought to liberate at most one vesicle per action potential in a probabilistic fashion, rendering synaptic transmission unreliable. However, the simultaneous release of several vesicles, or multivesicular release (MVR), represents a simple mechanism to overcome the intrinsic unreliability of synaptic transmission. MVR was initially identified at specialized synapses but is now known to be common throughout the brain. MVR determines the temporal and spatial dispersion of transmitter, controls the extent of receptor activation, and contributes to adapting synaptic strength during plasticity and neuromodulation. MVR consequently represents a widespread mechanism that extends the dynamic range of synaptic processing.
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... Although it has been demonstrated that action potentials induce univesicular release of neurotransmitter at some synaptic junctions (Arancio et al., 1994), the presence of multivesicular release is a more plausible scenario that, in addition to the sub-saturation of synaptic receptors, explains variability in paired pulse responses (Hessler et al., 1993, Mainen et al., 1999, McAllister and Stevens, 2000, Oertner et al., 2002, Conti and Lisman, 2003. Facilitating LOT synapses could presumably exhibit the same multivesicular release of glutamate as facilitating CA1 Schaffer collateral synapses in hippocampus (Oertner et al., 2002, Ricci-Tersenghi et al., 2006. The similar smaller amplitudes as well as the frequency of occurrence in spontaneously occurring AMPAR events and mEPSCs suggest that the majority of spontaneous events collected were mediated by release of single vesicles in both synaptic populations. ...
The influence of anatomical, developmental and degenerative factors on the function of synaptically expressed ionotropic glutamate receptors was assessed in murine models. Recordings were obtained in whole cell configuration from principal cells in layer II of acutely prepared slices of anterior piriform cortex (APC). Synaptic currents mediated by AMPARs and NMDARs were elicited by evoked stimulation and isolated on the basis of differences in pharmacological and kinetic characteristics of each receptor type. The relative current contribution in synaptic populations was assessed by an NMDA/AMPA ratio calculated from measurement of evoked currents. AMPAR currents were characterized at single synapses by mEPSCs and response to minimal stimulation.
Afferent and intrinsic axonal fiber tracts were stimulated to elicit currents at lateral olfactory tract (LOT) and association (ASSN) synapses, two anatomically and physiologically distinct populations of synapses. Paired pulse responses at 50 ms ISI revealed differences in the amount of facilitation between both synaptic populations. Synaptic transmission mediated by AMPAR function was assessed by minimal stimulation and determined to be equivalent in amplitude between LOT and ASSN synapses, although differences in AMPAR kinetic characteristics were detected between pathways. The NMDA/AMPA ratio was decreased at LOT compared to ASSN synapses. Differences found in the relative NMDAR and AMPAR complement and similarities in AMPAR function suggest differences in NMDAR function between LOT and ASSN synapses. Kinetic differences detected in AMPAR-mediated currents suggest different AMPAR complements are also expressed at both pathways.
Synaptic receptor function was characterized in a mouse model for developmental intellectual disability, the Fmr1-KO. Synaptic NMDAR and AMPAR function was assessed at ASSN synapses in 3-6 month old Fmr1-KO and WT littermates. The NMDA/AMPA ratio was reduced at ASSN synapses of the Fmr1-KO and similar amplitudes in AMPAR-mediated mEPSCs were observed in both groups. No differences were observed in voltage sensitivities or kinetic characteristics of either NMDAR or AMPAR currents. These findings suggest a reduction in NMDAR function at these synapses in the Fmr1-KO compared to WT.
The effect of aging on NMDAR and AMPAR function was assessed at LOT and ASSN synapses in 3-28 month old mice. A significant reduction in AMPAR-mediated mEPSC amplitude was observed in 24-28 month old mice. No age related difference was detected in the NMDA/AMPA ratio or paired pulse ratio. These findings suggest that concomitant downregulation of AMPAR and NMDAR function occurs at both LOT and ASSN synapses in aged mice.
The relative and absolute function of NMDARs and AMPARs at LOT and ASSN synapses were found to be differentially affected in all three comparisons. Reduction of currents mediated by one or both synaptic receptor types were observed in all conditions. Hypofunction of one or both receptor type and the relative ratios thereof may explain specific characteristics of LTP induction and expression in APC, and learned behaviors mediated by this synaptic plasticity, in anatomical and etiological conditions.
... Umemiya et al. 1999, Conti and Lisman 2003, Ricci-Tersenghi et al. 2006). Our simulations indicate that in response to large, nonvariable numbers of glutamate molecules, the stochastic nature of NMDAR activation contributes little to the variability observed at high CV synapses. ...
... Our simulations indicate that in response to large, nonvariable numbers of glutamate molecules, the stochastic nature of NMDAR activation contributes little to the variability observed at high CV synapses. The high CV observed experimentally during MVR is instead likely mediated by presynaptic mechanisms, including vesicular glutamate content(Wilson et al. 2005) and number of vesicles released(Conti and Lisman 2003, Raghavachari and Lisman 2004, Ricci-Tersenghi et al. 2006. ...
The N-methyl D-aspartate receptor (NMDAR), a common glutamate receptor found throughout the brain, has long been implicated as the major mediator of the pathology seen after traumatic brain injury (TBI). However, given their critical role in physiologic function of neural networks, complete inhibition of these receptors is an unsuitable therapeutic strategy. Thus, further investigation into how these receptors respond to injury is required to identify more directed therapeutic targets. Here, we aimed to use two unique experimental models to further investigate the role of NMDARs in the neuronal response to TBI, with specific emphasis on the contribution of different NMDAR subtypes. TBI produces a unique disease paradigm containing mechanical and biochemical components, which can both affect NMDAR activity. We sought to isolate the effects of both these components and then to examine how they combine to create a unique injury response.
We utilized a recombinant system expressing known NMDAR subtypes to first examine the action of mechanical stretch on specific subtypes. We demonstrated that mechanosensitivity of the NMDAR is indeed dependent on its subunit composition, with the NR2B subunit conferring stretch sensitivity. Further, we were able to investigate the regulation of NR2B mechanosensitivity and found that a single PKC phosphorylation site on the NR2B C-terminal tail can critically control stretch sensitivity.
We next developed a computational model of a single dendritic spine to evaluate the patterns of activation among NMDAR subtypes in both physiologic and pathologic glutamatergic signaling. We demonstrate that the presence of multiple NMDAR subtypes on the dendritic spine enables the ability for a single synapse to produce unique responses to different glutamate inputs. Importantly, we discovered that injury induced release of synaptic glutamate vesicles results in enhanced contribution of NR2B containing receptors. Finally, we have shown that the collective effects of TBI can drastically enhance the calcium influx from synaptic and extrasynaptic NR1/NR2B-NMDARs, an NMDAR subtype known to mediate pro-death signaling. Together, our data demonstrates that the NR2B subunit represents a unique pathologic sensor for TBI, and could represent an intriguing target of manipulation in the development of improved TBI therapeutics.
... doi:10.1371/journal.pcbi.1002106.g009 may seem inconsistent with published reports, as multivesicular release is often reported with high values of CV calculated from miniature excitatory postsynaptic currents (mEPSCs) [78,79,80]. Our simulations indicate that in response to large, nonvariable numbers of glutamate molecules, the stochastic nature of NMDAR activation contributes little to the variability observed at high CV synapses. ...
... Our simulations indicate that in response to large, nonvariable numbers of glutamate molecules, the stochastic nature of NMDAR activation contributes little to the variability observed at high CV synapses. The high CV observed experimentally during MVR is instead likely mediated by presynaptic mechanisms, including vesicular glutamate content [81,82] and number of vesicles released [30,78,79]. Perhaps most interesting is the transition or shift in the activation of different NMDAR populations at the synapse for MVR (also reported in Santucci and Ragavachari, 2008) that can significantly impact the type and extent of downstream signaling. ...
... For a synapse dominated by NR1/NR2B-NMDARs, our simulations suggest that MVR, or other compensatory mechanisms, is necessary to improve the consistency of the signaling mediated through the synaptic NMDARs. It is interesting to note that several studies cite the increased frequency of MVR in immature neuronal cultures, where the expression of NR1/NR2B-NMDARs dominates [79,83]. Alternatively, if a synapse contains a majority of triheteromeric NMDARs, the synapse would have a broadened ability to respond more consistently to both UVR and MVR, although this synapse would still have limited ability to reliably detect NMDAR signaling for small, single vesicles containing less than approximately 1,000 molecules. ...
NMDA receptors (NMDARs) are the major mediator of the postsynaptic response during synaptic neurotransmission. The diversity of roles for NMDARs in influencing synaptic plasticity and neuronal survival is often linked to selective activation of multiple NMDAR subtypes (NR1/NR2A-NMDARs, NR1/NR2B-NMDARs, and triheteromeric NR1/NR2A/NR2B-NMDARs). However, the lack of available pharmacological tools to block specific NMDAR populations leads to debates on the potential role for each NMDAR subtype in physiological signaling, including different models of synaptic plasticity. Here, we developed a computational model of glutamatergic signaling at a prototypical dendritic spine to examine the patterns of NMDAR subtype activation at temporal and spatial resolutions that are difficult to obtain experimentally. We demonstrate that NMDAR subtypes have different dynamic ranges of activation, with NR1/NR2A-NMDAR activation sensitive at univesicular glutamate release conditions, and NR2B containing NMDARs contributing at conditions of multivesicular release. We further show that NR1/NR2A-NMDAR signaling dominates in conditions simulating long-term depression (LTD), while the contribution of NR2B containing NMDAR significantly increases for stimulation frequencies that approximate long-term potentiation (LTP). Finally, we show that NR1/NR2A-NMDAR content significantly enhances response magnitude and fidelity at single synapses during chemical LTP and spike timed dependent plasticity induction, pointing out an important developmental switch in synaptic maturation. Together, our model suggests that NMDAR subtypes are differentially activated during different types of physiological glutamatergic signaling, enhancing the ability for individual spines to produce unique responses to these different inputs.
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.
