Quantal analysis estimates docking site occupancy determining short‐term depression at hippocampal glutamatergic synapses

2021 ◽  
Author(s):  
Mamoru Tanaka ◽  
Takeshi Sakaba ◽  
Takafumi Miki
Keyword(s):  
Site Occupancy ◽  
Docking Site ◽  
Glutamatergic Synapses ◽  
Short Term ◽  
Quantal Analysis

scholarly journals A two-step docking site model predicting different short-term synaptic plasticity patterns

2018 ◽  
Vol 150 (8) ◽  
pp. 1107-1124 ◽  
Author(s):  
Camila Pulido ◽  
Alain Marty
Keyword(s):  
Action Potential ◽  
Action Potentials ◽  
Site Occupancy ◽  
Synaptic Strength ◽  
Docking Site ◽  
Short Term ◽  
Site Model ◽  
Step Model ◽  
One Step ◽  
Using Data

The strength of synaptic transmission varies during trains of presynaptic action potentials, notably because of the depletion of synaptic vesicles available for release. It has remained unclear why some synapses display depression over time, whereas others facilitate or show a facilitation and depression sequence. Here we compare the predictions of various synaptic models assuming that several docking/release sites are acting in parallel. These models show variation of docking site occupancy during trains of action potentials due to vesicular release and site replenishment, which give rise to changes in synaptic strength. To conform with recent studies, we assume an initial docking site occupancy of <1, thus permitting site occupancy to increase during action potential trains and facilitation to occur. We consider both a standard one-step model and a more elaborate model that assumes a predocked state (two-step model). Whereas the one-step model predicts monotonic changes of synaptic strength during a train, the two-step model allows nonmonotonic changes, including the often-observed facilitation/depression sequence. Both models predict a partitioning of parameter space between initially depressing and facilitating synapses. Using data obtained from interneuron synapses in the cerebellum, we demonstrate an unusual form of depression/facilitation sequence for very high release probability after prolonged depolarization-induced transmitter release. These results indicate a depletion of predocked vesicles in the two-step model. By permitting docking site occupancy to be <1 at rest, and by incorporating a separate predocked state, we reveal that docking site models can be expanded to mimic the large variety of time-dependent changes of synaptic strength that have been observed during action potential trains. Furthermore, the two-step model provides an effective framework to identify the specific mechanisms responsible for short-term changes in synaptic strength.

scholarly journals Familial Danish dementia young Knock-in rats expressing humanized APP and human Aβ show impaired pre and postsynaptic glutamatergic transmission

2021 ◽  
Author(s):  
Tao Yin ◽  
Wen Yao ◽  
Kelly A Norris ◽  
Luciano D'Adamio
Keyword(s):  
Glutamate Release ◽  
Amyloid Β ◽  
Integral Membrane Protein ◽  
Proteolytic Processing ◽  
Glutamatergic Synapses ◽  
Short Term ◽  
Adult Mice ◽  
Familial Danish Dementia ◽  
Collateral Pathway ◽  
Proteolytic Product

Familial British and Danish dementia (FBD and FDD) are two neurodegenerative disorders caused by mutations in the Integral membrane protein 2B (ITM2b). BRI2, the protein encoded by ITM2b, tunes excitatory synaptic transmission at both pre- and post-synaptic terminus. Too, BRI2 interacts with and modulates proteolytic processing of Amyloid-β precursor Protein (APP), whose mutations cause familial forms of Alzheimer disease (FAD). To study pathogenic mechanism triggered by the Danish mutation we generated rats carrying the Danish mutation into the rat Itm2b gene (Itm2bD rats). Given the BRI2/APP interaction and the widely accepted relevance of human Aβ, a proteolytic product of APP, to AD, Itm2bD rats were engineered to express two humanized App alleles, to produce human Aβ. Here, we studied young Itm2bD rats to investigate early pathogenic changes. We found that peri-adolescent Itm2bD rats present subtle changes in human Aβ levels along with decreased spontaneous glutamate release and AMPAR-mediated responses, but increased short-term synaptic facilitation in the hippocampal Schaeffer-collateral pathway. These changes are similar to those observed in adult mice producing rodent Aβ and carrying either the Danish or British mutations into the mouse Itm2b gene. Collectively, the data show that the pathogenic Danish mutation alters the physiological function of BRI2 at glutamatergic synapses; these functional alterations are detected across species and occur early in life. Future studies will be needed to determine whether this phenomenon represents an early pathogenic event in human dementia.

scholarly journals Diversity of excitatory release sites

2021 ◽  
Author(s):  
Maria Rita Karlocai ◽  
Judit Heredi ◽  
Tünde Benedek ◽  
Noemi Holderith ◽  
Andrea Lorincz ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Pyramidal Cells ◽  
Molecular Heterogeneity ◽  
Glutamatergic Synapses ◽  
Large Variability ◽  
Ca1 Pyramidal Cells ◽  
Hippocampal Ca1 ◽  
Quantal Analysis ◽  
Fast Spiking ◽  
Active Zones

AbstractThe molecular mechanisms underlying the diversity of cortical glutamatergic synapses is still only partially understood. Here, we tested the hypothesis that presynaptic active zones (AZs) are constructed from molecularly uniform, independent release sites (RSs), the number of which scales linearly with the AZ size. Paired recordings between hippocampal CA1 pyramidal cells and fast-spiking interneurons followed by quantal analysis demonstrate large variability in the number of RSs (N) at these connections. High resolution molecular analysis of functionally characterized synapses reveals highly variable Munc13-1 content of AZs that possess the same N. Replica immunolabeling also shows a 3-fold variability in the Munc13-1 content of AZs of identical size. Munc13-1 is clustered within the AZs; cluster size and density are also variable. Our results provide evidence for quantitative molecular heterogeneity of RSs and support a model in which the AZ is built up from variable numbers of molecularly heterogeneous, but independent RSs.

scholarly journals TRPC channels regulate Ca2+-signaling and short-term plasticity of fast glutamatergic synapses

PLoS Biology ◽  
2019 ◽  
Vol 17 (9) ◽  
pp. e3000445 ◽  
Author(s):  
Yvonne Schwarz ◽  
Katharina Oleinikov ◽  
Barbara Schindeldecker ◽  
Amanda Wyatt ◽  
Petra Weißgerber ◽  
...  
Keyword(s):  
Trpc Channels ◽  
Glutamatergic Synapses ◽  
Short Term ◽  
Short Term Plasticity

scholarly journals Cadmium opens GluK2 kainate receptors with cysteine substitutions at the M3 helix bundle crossing

2018 ◽  
Vol 151 (4) ◽  
pp. 435-451 ◽  
Author(s):  
Timothy J. Wilding ◽  
James E. Huettner
Keyword(s):  
Conformational Changes ◽  
Site Occupancy ◽  
Kainate Receptors ◽  
Inhibitory Synapses ◽  
Side Chains ◽  
Glutamatergic Synapses ◽  
Channel Opening ◽  
The Central Nervous System ◽  
Excitatory Neurotransmission ◽  
Ion Pore

Kainate receptors are ligand-gated ion channels that have two major roles in the central nervous system: they mediate a postsynaptic component of excitatory neurotransmission at some glutamatergic synapses and modulate transmitter release at both excitatory and inhibitory synapses. Accumulating evidence implicates kainate receptors in a variety of neuropathologies, including epilepsy, psychiatric disorders, developmental delay, and cognitive impairment. Here, to gain a deeper understanding of the conformational changes associated with agonist binding and channel opening, we generate a series of Cys substitutions in the GluK2 kainate receptor subunit, focusing on the M3 helices that line the ion pore and form the bundle-crossing gate at the extracellular mouth of the channel. Exposure to 50 µM Cd produces direct activation of homomeric mutant channels bearing Cys substitutions in (A657C), or adjacent to (L659C), the conserved SYTANLAAF motif. Activation by Cd is occluded by modification with 2-aminoethyl MTS (MTSEA), indicating that Cd binds directly and specifically to the substituted cysteines. Cd potency for the A657C mutation (EC50 = 10 µM) suggests that binding involves at least two coordinating residues, whereas weaker Cd potency for L659C (EC50 = 2 mM) implies that activation does not require tight coordination by multiple side chains for this substitution. Experiments with heteromeric and chimeric channels indicate that activation by Cd requires Cys substitution at only two of the four subunits within a tetrameric receptor and that activation is similar for substitution within subunits in either the A/C or B/D conformations. We develop simple kinetic models for the A657C substitution that reproduce several features of Cd activation as well as the low-affinity inhibition observed at higher Cd concentrations (5–20 mM). Together, these results demonstrate rapid and reversible channel activation, independent of agonist site occupancy, upon Cd binding to Cys side chains at two specific locations along the GluK2 inner helix.

scholarly journals Quantal Fluctuations in Central Mammalian Synapses: Functional Role of Vesicular Docking Sites

2017 ◽  
Vol 97 (4) ◽  
pp. 1403-1430 ◽  
Author(s):  
Camila Pulido ◽  
Alain Marty
Keyword(s):  
Neuromuscular Junction ◽  
Active Zone ◽  
Synaptic Vesicles ◽  
Site Occupancy ◽  
Physical Nature ◽  
Frog Neuromuscular Junction ◽  
Docking Site ◽  
Single Action ◽  
Docking Sites ◽  
Central Synapses

Quantal fluctuations are an integral part of synaptic signaling. At the frog neuromuscular junction, Bernard Katz proposed that quantal fluctuations originate at “reactive sites” where specific structures of the presynaptic membrane interact with synaptic vesicles. However, the physical nature of reactive sites has remained unclear, both at the frog neuromuscular junction and at central synapses. Many central synapses, called simple synapses, are small structures containing a single presynaptic active zone and a single postsynaptic density of receptors. Several lines of evidence indicate that simple synapses may release several synaptic vesicles in response to a single action potential. However, in some synapses at least, each release event activates a significant fraction of the postsynaptic receptors, giving rise to a sublinear relation between vesicular release and postsynaptic current. Partial receptor saturation as well as synaptic jitter gives to simple synapse signaling the appearance of a binary process. Recent investigations of simple synapses indicate that the number of released vesicles follows binomial statistics, with a maximum reflecting the number of docking sites present in the active zone. These results suggest that at central synapses, vesicular docking sites represent the reactive sites proposed by Katz. The macromolecular architecture and molecular composition of docking sites are presently investigated with novel combinations of techniques. It is proposed that variations in docking site numbers are central in defining intersynaptic variability and that docking site occupancy is a key parameter regulating short-term synaptic plasticity.

scholarly journals Short-Term Effects of Moderate- to High-Severity Wildfire on a Disturbance-Dependent Flycatcher in Northwest California

The Auk ◽  
2003 ◽  
Vol 120 (4) ◽  
pp. 1102-1113
Author(s):  
Timothy D. Meehan ◽  
T. Luke George
Keyword(s):  
Odds Ratio ◽  
Forest Regeneration ◽  
Site Occupancy ◽  
Negative Effects ◽  
Short Term ◽  
Burned Areas ◽  
High Severity ◽  
The Relationship ◽  
Nest Loss ◽  
Short Term Effects

Abstract Previous studies have shown Olive-sided Flycatchers (Contopus cooperi) to be associated with burned forest, which suggests that wildfire is beneficial to the species. To examine that more closely, we studied the short-term effects (first two years after disturbance) of moderate- to high-severity wildfire on Olive-sided Flycatchers breeding in northwestern California. During summers of 2000 and 2001, we investigated distribution of and compared the relative nest loss, foraging rates, and aerial arthropod biomass at Olive-sided Flycatcher territories in burned and adjacent unburned forest. The probability of postfire site occupancy was best predicted by the presence of pre-existing forest edges (odds ratio = 8:1). Probability of relative nest loss was much higher in the presence of fire (odds ratio = 9:1). Adult female peak foraging rates were nearly twice as high in unburned (2000 = 2.1 attacks min−1, 2001 = 2.5) as in burned (2000 = 1.0, 2001 = 1.5) territories, and relative aerial arthropod biomass was nearly twice as high in unburned (2000 = 1,909 mg 2 m−2 40 days−1, 2001 = 3,200) as in burned (2000 = 1,105, 2001 = 1,751) territories. Although Olive-sided Flycatchers occupied recently burned areas, fire had apparent negative effects on reproduction. Poor reproduction appeared to be partially related to reduced food availability in recently burned areas. Our data suggest a need for detailed investigations of the relationship between Olive-sided Flycatchers and wildfire as postfire forest regeneration progresses.

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