scholarly journals A theory of synaptic transmission

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Bin Wang ◽  
Olga K Dudko
Keyword(s):  
Action Potential ◽  
Synaptic Transmission ◽  
Neurotransmitter Release ◽  
Transmission Rate ◽  
Scaling Law ◽  
Synaptic Function ◽  
Fine Tuning ◽  
Chemical Synapse ◽  
Existing Data

Rapid and precise neuronal communication is enabled through a highly synchronous release of signaling molecules neurotransmitters within just milliseconds of the action potential. Yet neurotransmitter release lacks a theoretical framework that is both phenomenologically accurate and mechanistically realistic. Here, we present an analytic theory of the action-potential-triggered neurotransmitter release at the chemical synapse. The theory is demonstrated to be in detailed quantitative agreement with existing data on a wide variety of synapses from electrophysiological recordings in vivo and fluorescence experiments in vitro. Despite up to ten orders of magnitude of variation in the release rates among the synapses, the theory reveals that synaptic transmission obeys a simple, universal scaling law, which we confirm through a collapse of the data from strikingly diverse synapses onto a single master curve. This universality is complemented by the ability of the theory to readily extract, through a fit to the data, the kinetic and energetic parameters that uniquely identify each synapse. The theory provides a means to detect cooperativity among the SNARE complexes that mediate vesicle fusion and reveals such cooperativity in several existing data sets. The theory is further applied to establish connections between molecular constituents of synapses and synaptic function. The theory allows competing hypotheses of short-term plasticity to be tested and identifies the regimes where particular mechanisms of synaptic facilitation dominate or, conversely, fail to account for the existing data for the paired-pulse ratio. The derived trade-off relation between the transmission rate and fidelity shows how transmission failure can be controlled by changing the microscopic properties of the vesicle pool and SNARE complexes. The established condition for the maximal synaptic efficacy reveals that no fine tuning is needed for certain synapses to maintain near-optimal transmission. We discuss the limitations of the theory and propose possible routes to extend it. These results provide a quantitative basis for the notion that the molecular-level properties of synapses are crucial determinants of the computational and information-processing functions in synaptic transmission.

scholarly journals A Theory of Synaptic Transmission

2020 ◽  
Author(s):  
Bin Wang ◽  
Olga Dudko
Keyword(s):  
Experimental Data ◽  
Action Potential ◽  
Synaptic Transmission ◽  
Neurotransmitter Release ◽  
Molecular Mechanisms ◽  
Synaptic Function ◽  
Universal Curve ◽  
Universal Scaling ◽  
Neuronal Communication ◽  
Key Characteristics

Rapid and precise neuronal communication is enabled through a highly synchronous release of signaling molecules neurotransmitters into the synapse within just milliseconds of the action potential. We present an analytic theory that captures general principles of synaptic transmission while generating concrete predictions for particular synapses. A universal scaling is established, and demonstrated through a collapse of experimental data from different synapses onto a universal curve. The theory shows how key characteristics of synaptic function -- plasticity, fidelity, and efficacy -- emerge from molecular mechanisms of neurotransmitter release machinery.

scholarly journals Structural elements that underlie Doc2β function during asynchronous synaptic transmission

2015 ◽  
Vol 112 (31) ◽  
pp. E4316-E4325 ◽  
Author(s):  
Renhao Xue ◽  
Jon D. Gaffaney ◽  
Edwin R. Chapman
Keyword(s):  
Plasma Membrane ◽  
Synaptic Transmission ◽  
Neurotransmitter Release ◽  
Lipid Binding ◽  
Slow Phase ◽  
Structural Elements ◽  
Excitatory Postsynaptic Current ◽  
Synaptotagmin 1 ◽  
Asynchronous Release

Double C2-like domain-containing proteins alpha and beta (Doc2α and Doc2β) are tandem C2-domain proteins proposed to function as Ca2+ sensors for asynchronous neurotransmitter release. Here, we systematically analyze each of the negatively charged residues that mediate binding of Ca2+ to the β isoform. The Ca2+ ligands in the C2A domain were dispensable for Ca2+-dependent translocation to the plasma membrane, with one exception: neutralization of D220 resulted in constitutive translocation. In contrast, three of the five Ca2+ ligands in the C2B domain are required for translocation. Importantly, translocation was correlated with the ability of the mutants to enhance asynchronous release when overexpressed in neurons. Finally, replacement of specific Ca2+/lipid-binding loops of synaptotagmin 1, a Ca2+ sensor for synchronous release, with corresponding loops from Doc2β, resulted in chimeras that yielded slower kinetics in vitro and slower excitatory postsynaptic current decays in neurons. Together, these data reveal the key determinants of Doc2β that underlie its function during the slow phase of synaptic transmission.

α-Adrenoceptive Dual Modulation of Inhibitory GABAergic Inputs to Purkinje Cells in the Mouse Cerebellum

2006 ◽  
Vol 95 (2) ◽  
pp. 700-708 ◽  
Author(s):  
Moritoshi Hirono ◽  
Kunihiko Obata
Keyword(s):  
Synaptic Transmission ◽  
Purkinje Cells ◽  
Cerebellar Cortex ◽  
Neurotransmitter Release ◽  
Gaba Receptor ◽  
Fine Tuning ◽  
Inhibitory Neurotransmitter ◽  
Inhibitory Synaptic Transmission ◽  
Pulse Ratio ◽  
Adrenoceptor Agonist

Noradrenaline (NA) modulates synaptic transmission in various sites of the CNS. In the cerebellar cortex, several studies have revealed that NA enhances inhibitory synaptic transmission by β-adrenoceptor–and cyclic AMP–dependent pathways. However, the effects of α-adrenoceptor activation on cerebellar inhibitory neurotransmission have not yet been fully elucidated. Therefore we investigated the effects of the α1- or α2-adrenoceptor agonist on inhibitory postsynaptic currents (IPSCs) recorded from mouse Purkinje cells (PCs). We found that the nonselective α-adrenoceptor agonist 6-fluoro-norepinephrine increased both the frequency and amplitude of spontaneous IPSCs (sIPSCs). This enhancement was mostly mimicked by the selective α1-adrenoceptor agonist phenylephrine (PE). PE also enhanced the amplitude of evoked IPSCs (eIPSCs) and increased the frequency but not the amplitude of miniature IPSCs (mIPSCs). Moreover, PE decreased the paired-pulse ratio of eIPSCs and did not change γ-aminobutyric acid (GABA) receptor sensitivity in PCs. Conversely, the selective α2-adrenoceptor agonist clonidine significantly reduced both the frequency and the amplitude of sIPSCs. Neither eIPSCs nor mIPSCs were affected by clonidine. Furthermore, presynaptic cell-attached recordings showed that spontaneous activity of GABAergic interneurons was enhanced by PE but reduced by clonidine. These results suggest that NA enhances inhibitory neurotransmitter release by α1-adrenoceptors, which are expressed in presynaptic terminals and somatodendritic domains, whereas NA suppresses the excitability of interneurons by α2-adrenoceptors, which are expressed in presynaptic somatodendritic domains. Thus cerebellar α-adrenoceptors play roles in a presynaptic dual modulation of GABAergic inputs from interneurons to PCs, thereby providing a likely mechanism for the fine-tuning of information flow in the cerebellar cortex.

scholarly journals Synaptic Scaling Stabilizes Persistent Activity Driven by Asynchronous Neurotransmitter Release

2011 ◽  
Vol 23 (4) ◽  
pp. 927-957 ◽  
Author(s):  
Vladislav Volman ◽  
Richard C. Gerkin
Keyword(s):  
Synaptic Transmission ◽  
Neurotransmitter Release ◽  
Hippocampal Neurons ◽  
Computational Models ◽  
Essential Feature ◽  
Network Activity ◽  
Synaptic Connectivity ◽  
The Stability ◽  
Synaptic Drive

Small networks of cultured hippocampal neurons respond to transient stimulation with rhythmic network activity (reverberation) that persists for several seconds, constituting an in vitro model of synchrony, working memory, and seizure. This mode of activity has been shown theoretically and experimentally to depend on asynchronous neurotransmitter release (an essential feature of the developing hippocampus) and is supported by a variety of developing neuronal networks despite variability in the size of populations (10–200 neurons) and in patterns of synaptic connectivity. It has previously been reported in computational models that “small-world” connection topology is ideal for the propagation of similar modes of network activity, although this has been shown only for neurons utilizing synchronous (phasic) synaptic transmission. We investigated how topological constraints on synaptic connectivity could shape the stability of reverberations in small networks that also use asynchronous synaptic transmission. We found that reverberation duration in such networks was resistant to changes in topology and scaled poorly with network size. However, normalization of synaptic drive, by reducing the variance of synaptic input across neurons, stabilized reverberation in such networks. Our results thus suggest that the stability of both normal and pathological states in developing networks might be shaped by variance-normalizing constraints on synaptic drive. We offer an experimental prediction for the consequences of such regulation on the behavior of small networks.

Modulation of Transmitter Release by Action Potential Duration at the Hippocampal CA3-CA1 Synapse

1999 ◽  
Vol 81 (1) ◽  
pp. 288-298 ◽  
Author(s):  
Jing Qian ◽  
Peter Saggau
Keyword(s):  
Action Potential ◽  
Synaptic Transmission ◽  
Action Potential Duration ◽  
Transmitter Release ◽  
Neurotransmitter Release ◽  
Channel Blocker ◽  
Transmission Curve ◽  
Similar Reduction ◽  
Voltage Dependent ◽  
Hippocampal Ca3

Qian, Jing and Peter Saggau. Modulation of transmitter release by action potential duration at the hippocampal CA3-CA1 synapse. J. Neurophysiol. 81: 288–298, 1999. Presynaptic Ca2+ influx through voltage-dependent Ca2+ channels triggers neurotransmitter release. Action potential duration plays a determinant role in the dynamics of presynaptic Ca2+ influx. In this study, the presynaptic Ca2+ influx was optically measured with a low-affinity Ca2+ indicator (Furaptra). The effect of action potential duration on Ca2+ influx and transmitter release was investigated. The K+ channel blocker 4-aminopyridine (4-AP) was applied to broaden the action potential and thereby increase presynaptic Ca2+ influx. This increase of Ca2+ influx appeared to be much less effective in enhancing transmitter release than raising the extracellular Ca2+ concentration. 4-AP did not change the Ca2+ dependence of transmitter release but instead shifted the synaptic transmission curve toward larger total Ca2+ influx. These results suggest that changing the duration of Ca2+ influx is not equivalent to changing its amplitude in locally building up an effective Ca2+ concentration near the Ca2+ sensor of the release machinery. Furthermore, in the presence of 4-AP, the N-type Ca2+ channel blocker ωCgTx GVIA was much less effective in blocking transmitter release. This phenomenon was not simply due to a saturation of the release machinery by the increased overall Ca2+ influx because a similar reduction of Ca2+ influx by application of the nonspecific Ca2+ channel blocker Cd2+ resulted in much more inhibition of transmitter release. Rather, the different potencies of ω-CgTx GVIA and Cd2+ in inhibiting transmitter release suggest that the Ca2+ sensor is possibly located at a distance from a cluster of Ca2+ channels such that it is sensitive to the location of Ca2+ channels within the cluster.

scholarly journals Slob, a Slowpoke channel–binding protein, modulates synaptic transmission

2011 ◽  
Vol 137 (2) ◽  
pp. 225-238 ◽  
Author(s):  
Huifang Ma ◽  
Jiaming Zhang ◽  
Irwin B. Levitan
Keyword(s):  
Action Potential ◽  
Synaptic Transmission ◽  
Muscle Cell ◽  
Binding Protein ◽  
P Element ◽  
Macromolecular Complex ◽  
Functional Consequences ◽  
Targeted Expression

Modulation of ion channels by regulatory proteins within the same macromolecular complex is a well-accepted concept, but the physiological consequences of such modulation are not fully understood. Slowpoke (Slo), a potassium channel critical for action potential repolarization and transmitter release, is regulated by Slo channel–binding protein (Slob), a Drosophila melanogaster Slo (dSlo) binding partner. Slob modulates the voltage dependence of dSlo channel activation in vitro and exerts similar effects on the dSlo channel in Drosophila central nervous system neurons in vivo. In addition, Slob modulates action potential duration in these neurons. Here, we investigate further the functional consequences of the modulation of the dSlo channel by Slob in vivo, by examining larval neuromuscular synaptic transmission in flies in which Slob levels have been altered. In Slob-null flies generated through P-element mutagenesis, as well as in Slob knockdown flies generated by RNA interference (RNAi), we find an enhancement of synaptic transmission but no change in the properties of the postsynaptic muscle cell. Using targeted transgenic rescue and targeted expression of Slob-RNAi, we find that Slob expression in neurons (but not in the postsynaptic muscle cell) is critical for its effects on synaptic transmission. Furthermore, inhibition of dSlo channel activity abolishes these effects of Slob. These results suggest that presynaptic Slob, by regulating dSlo channel function, participates in the modulation of synaptic transmission.

scholarly journals Excitatory synaptic transmission and network activity are depressed following mechanical injury in cortical neurons

2011 ◽  
Vol 105 (5) ◽  
pp. 2350-2363 ◽  
Author(s):  
Paulette B. Goforth ◽  
Jianhua Ren ◽  
Benjamin S. Schwartz ◽  
Leslie S. Satin
Keyword(s):  
Synaptic Transmission ◽  
Cortical Neurons ◽  
Mechanical Injury ◽  
Synaptic Function ◽  
Transient Increase ◽  
Excitatory Synaptic Transmission ◽  
Network Activity ◽  
Free Calcium ◽  
Post Injury

In vitro and in vivo traumatic brain injury (TBI) alter the function and expression of glutamate receptors, yet the combined effect of these alterations on cortical excitatory synaptic transmission is unclear. We examined the effect of in vitro mechanical injury on excitatory synaptic function in cultured cortical neurons by assaying synaptically driven intracellular free calcium ([Ca2+]i) oscillations in small neuronal networks as well as spontaneous and miniature excitatory postsynaptic currents (mEPSCs). We show that injury decreased the incidence and frequency of spontaneous neuronal [Ca2+]i oscillations for at least 2 days post-injury. The amplitude of the oscillations was reduced immediately and 2 days post-injury, although a transient rebound at 4 h post-injury was observed due to increased activity of N-methyl-d-aspartate (NMDARs) and calcium-permeable α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptors (CP-AMPARs). Increased CP-AMPAR function was abolished by the inhibition of protein synthesis. In parallel, mEPSC amplitude decreased immediately, 4 h, and 2 days post-injury, with a transient increase in the contribution of synaptic CP-AMPARs observed at 4 h post-injury. Decreased mEPSC amplitude was evident after injury, even if NMDARs and CP-AMPARs were blocked pharmacologically, suggesting the decrease reflected alterations in synaptic Glur2-containing, calcium-impermeable AMPARs. Despite the transient increase in CP-AMPAR activity that we observed, the overriding effect of mechanical injury was long-term depression of excitatory neurotransmission that would be expected to contribute to the cognitive deficits of TBI.

Role of cyclooxygenase activation and prostaglandins in antigen-induced excitability changes of bronchial parasympathetic ganglia neurons

2003 ◽  
Vol 284 (4) ◽  
pp. L581-L587 ◽  
Author(s):  
Radhika Kajekar ◽  
Bradley J. Undem ◽  
Allen C. Myers
Keyword(s):  
Guinea Pig ◽  
Action Potential ◽  
Synaptic Transmission ◽  
Cyclooxygenase Inhibitors ◽  
Antigen Challenge ◽  
Parasympathetic Nerve ◽  
Parasympathetic Ganglia ◽  
Parasympathetic Ganglion ◽  
Ganglion Neurons

In vitro antigen challenge has multiple effects on the excitability of guinea pig bronchial parasympathetic ganglion neurons, including depolarization, causing phasic neurons to fire with a repetitive action potential pattern and potentiating synaptic transmission. In the present study, guinea pigs were passively sensitized to the antigen ovalbumin. After sensitization, the bronchi were prepared for in vitro electrophysiological intracellular recording of parasympathetic ganglia neurons to investigate the contribution of cyclooxygenase activation and prostanoids on parasympathetic nerve activity. Cyclooxygenase inhibition with either indomethacin or piroxicam before in vitro antigen challenge blocked the change in accommodation. These cyclooxygenase inhibitors also blocked the release of prostaglandin D2 (PGD2) from bronchial tissue during antigen challenge. We also determined that PGE2 and PGD2 decreased the duration of the action potential after hyperpolarization, whereas PGF2α potentiated synaptic transmission. Thus prostaglandins released during antigen challenge have multiple effects on the excitability of guinea pig bronchial parasympathetic ganglia neurons, which may consequently affect the output from these neurons and thereby alter parasympathetic tone in the lower airways.

scholarly journals Neuronal Glycoprotein M6a: An Emerging Molecule in Chemical Synapse Formation and Dysfunction

2021 ◽  
Vol 13 ◽  
Author(s):  
Antonella León ◽  
Gabriela I. Aparicio ◽  
Camila Scorticati
Keyword(s):  
Large Scale ◽  
Molecular Mechanisms ◽  
Neuronal Development ◽  
Synapse Formation ◽  
Disease Risk ◽  
Protein Complexes ◽  
Synaptic Function ◽  
Chemical Synapse ◽  
Gene Target

The cellular and molecular mechanisms underlying neuropsychiatric and neurodevelopmental disorders show that most of them can be categorized as synaptopathies—or damage of synaptic function and plasticity. Synaptic formation and maintenance are orchestrated by protein complexes that are in turn regulated in space and time during neuronal development allowing synaptic plasticity. However, the exact mechanisms by which these processes are managed remain unknown. Large-scale genomic and proteomic projects led to the discovery of new molecules and their associated variants as disease risk factors. Neuronal glycoprotein M6a, encoded by the GPM6A gene is emerging as one of these molecules. M6a has been involved in neuron development and synapse formation and plasticity, and was also recently proposed as a gene-target in various neuropsychiatric disorders where it could also be used as a biomarker. In this review, we provide an overview of the structure and molecular mechanisms by which glycoprotein M6a participates in synapse formation and maintenance. We also review evidence collected from patients carrying mutations in the GPM6A gene; animal models, and in vitro studies that together emphasize the relevance of M6a, particularly in synapses and in neurological conditions.

scholarly journals Characterization of age-related changes in synaptic transmission onto F344 rat basal forebrain cholinergic neurons using a reduced synaptic preparation

2014 ◽  
Vol 111 (2) ◽  
pp. 273-286 ◽  
Author(s):  
William H. Griffith ◽  
Dustin W. DuBois ◽  
Annette Fincher ◽  
Kathryn A. Peebles ◽  
Jennifer L. Bizon ◽  
...  
Keyword(s):  
Synaptic Transmission ◽  
Basal Forebrain ◽  
Water Maze ◽  
Cholinergic Neurons ◽  
Cognitive Status ◽  
Synaptic Function ◽  
Male Rats ◽  
Patch Clamp Recording ◽  
Age Related

Basal forebrain (BF) cholinergic neurons participate in a number of cognitive processes that become impaired during aging. We previously found that age-related enhancement of Ca2+ buffering in rat cholinergic BF neurons was associated with impaired performance in the water maze spatial learning task (Murchison D, McDermott AN, Lasarge CL, Peebles KA, Bizon JL, and Griffith WH. J Neurophysiol 102: 2194–2207, 2009). One way that altered Ca2+ buffering could contribute to cognitive impairment involves synaptic function. In this report we show that synaptic transmission in the BF is altered with age and cognitive status. We have examined the properties of spontaneous postsynaptic currents (sPSCs) in cholinergic BF neurons that have been mechanically dissociated without enzymes from behaviorally characterized F344 rats. These isolated neurons retain functional presynaptic terminals on their somata and proximal dendrites. Using whole cell patch-clamp recording, we show that sPSCs and miniature PSCs are predominately GABAergic (bicuculline sensitive) and in all ways closely resemble PSCs recorded in a BF in vitro slice preparation. Adult (4–7 mo) and aged (22–24 mo) male rats were cognitively assessed using the water maze. Neuronal phenotype was identified post hoc using single-cell RT-PCR. The frequency of sPSCs was reduced during aging, and this was most pronounced in cognitively impaired subjects. This is the same population that demonstrated increased intracellular Ca2+ buffering. We also show that increasing Ca2+ buffering in the synaptic terminals of young BF neurons can mimic the reduced frequency of sPSCs observed in aged BF neurons.

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