scholarly journals Calcium-permeable AMPA receptors mediate timing-dependent LTP elicited by 6 coincident action potentials at Schaffer collateral-CA1 synapses

2019 ◽  
Author(s):  
Efrain A. Cepeda-Prado ◽  
Babak Khodaie ◽  
Gloria D. Quiceno ◽  
Swantje Beythien ◽  
Volkmar Leßmann ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Action Potential ◽  
Low Frequency ◽  
Long Term Potentiation ◽  
Spike Timing ◽  
High Frequency Stimulation ◽  
Single Trial ◽  
Schaffer Collateral ◽  
Frequency Stimulation

AbstractActivity-dependent synaptic plasticity in neuronal circuits represents a cellular model of memory formation. Such changes can be elicited by repeated high-frequency stimulation inducing long-term potentiation (LTP), or by low frequency stimulation induced long-term depression (LTD). Spike timing-dependent plasticity (STDP) can induce equally robust long-lasting timing-dependent LTP (t-LTP) in response to low frequency repeats of coincident action potential (AP) firing in presynaptic cells followed by postsynaptic neurons. Conversely, this stimulation can lead to t-LTD if the postsynaptic spike precedes the presynaptic action potential. STDP is best suited to investigate synaptic plasticity mechanisms at the single cell level. Commonly, STDP paradigms relying on 25-100 repeats of coincident pre- and postsynaptic firing are used to elicit t-LTP or t-LTD. However, the minimum number of repeats required for successful STDP induction, which could account for fast single trial learning in vivo, is barely explored. Here, we examined low repeat STDP at Schaffer collateral-CA1 synapses by pairing one presynaptic AP with either one postsynaptic AP (1:1 t-LTP) or a burst of 4 APs (1:4 t-LTP). We found 3-6 repeats to be sufficient to elicit t-LTP. Postsynaptic Ca2+ elevation for 1:1 t-LTP required NMDARs and L-type VGCCs, while 1:4 t-LTP depended on metabotropic GluR and ryanodine receptor signaling. Surprisingly, both 6x t-LTP variants were strictly dependent on activation of postsynaptic Ca2+-permeable AMPARs. Both t-LTP forms were regulated differentially by dopamine receptors, but occurred independent from BDNF/TrkB signaling. Our data show that synaptic changes induced by only 3-6 repeats of mild STDP stimulation occuring in ≤10 s can take place on time scales observed also during single trial learning.

Coexistence of Muscarinic Long-Term Depression With Electrically Induced Long-Term Potentiation and Depression at CA3–CA1 Synapses

2006 ◽  
Vol 96 (6) ◽  
pp. 3114-3121 ◽  
Author(s):  
Eve McCutchen ◽  
Cary L. Scheiderer ◽  
Lynn E. Dobrunz ◽  
Lori L. McMahon
Keyword(s):  
Synaptic Plasticity ◽  
Low Frequency ◽  
Long Term Potentiation ◽  
Receptor Activation ◽  
High Frequency Stimulation ◽  
Muscarinic Agonist ◽  
Long Term Depression ◽  
Term Potentiation ◽  
Frequency Stimulation

Our laboratory recently characterized a form of long-term depression (LTD) at CA3–CA1 synapses mediated by M1 muscarinic receptors (mAChRs), termed muscarinic LTD (mLTD). mLTD is both activity and NMDAR dependent, characteristics shared by forms of synaptic plasticity thought to be relevant to learning and memory, including long-term potentiation (LTP) induced by high-frequency stimulation (HFS-LTP) and long-term depression induced by low-frequency stimulation (LFS-LTD). However, it remains unclear whether mLTD can occur sequentially with these electrically induced forms of hippocampal plasticity or whether mLTD might interact with them. The first goal of this study was to examine the interplay of mLTD and HFS-LTP. We report that mLTD expression does not alter subsequent induction of HFS-LTP and, further, at synapses expressing HFS-LTP, mLTD can mediate a novel form of depotentiation. The second goal was to determine whether mLTD would alter LFS-LTD induction and/or expression. Although we show that mLTD is occluded by saturation of LFS-LTD, suggesting mechanistic similarity between these two plasticities, saturation of mLTD does not occlude LFS-LTD. Surprisingly, however, the LFS-LTD that follows cholinergic receptor activation is NMDAR independent, indicating that application of muscarinic agonist induces a change in the induction mechanism required for LFS-LTD. These data demonstrate that mLTD can coexist with electrically induced forms of synaptic plasticity and support the hypothesis that mLTD is one of the mechanisms by which the cholinergic system modulates hippocampal function.

scholarly journals Tau- but not Aß -pathology enhances NMDAR-dependent depotentiation in AD-mouse models

2019 ◽  
Vol 7 (1) ◽  
Author(s):  
Enrico Faldini ◽  
Tariq Ahmed ◽  
Luc Bueé ◽  
David Blum ◽  
Detlef Balschun
Keyword(s):  
Synaptic Plasticity ◽  
Transgenic Mice ◽  
Mouse Models ◽  
Long Term Potentiation ◽  
High Frequency Stimulation ◽  
Synaptic Loss ◽  
Ca1 Region ◽  
Term Potentiation ◽  
Frequency Stimulation

AbstractMany mouse models of Alzheimer’s disease (AD) exhibit impairments in hippocampal long-term-potentiation (LTP), seemingly corroborating the strong correlation between synaptic loss and cognitive decline reported in human studies. In other AD mouse models LTP is unaffected, but other defects in synaptic plasticity may still be present. We recently reported that THY-Tau22 transgenic mice, that overexpress human Tau protein carrying P301S and G272 V mutations and show normal LTP upon high-frequency-stimulation (HFS), develop severe changes in NMDAR mediated long-term-depression (LTD), the physiological counterpart of LTP. In the present study, we focused on putative effects of AD-related pathologies on depotentiation (DP), another form of synaptic plasticity. Using a novel protocol to induce DP in the CA1-region, we found in 11–15 months old male THY-Tau22 and APPPS1–21 transgenic mice that DP was not deteriorated by Aß pathology while significantly compromised by Tau pathology. Our findings advocate DP as a complementary form of synaptic plasticity that may help in elucidating synaptic pathomechanisms associated with different types of dementia.

scholarly journals Cholecystokinin release triggered by NMDA receptors produces LTP and sound–sound associative memory

2019 ◽  
Vol 116 (13) ◽  
pp. 6397-6406 ◽  
Author(s):  
Xi Chen ◽  
Xiao Li ◽  
Yin Ting Wong ◽  
Xuejiao Zheng ◽  
Haitao Wang ◽  
...  
Keyword(s):  
Associative Learning ◽  
Associative Memory ◽  
High Frequency ◽  
Low Frequency ◽  
Long Term Potentiation ◽  
High Frequency Stimulation ◽  
Low Frequency Stimulation ◽  
Term Potentiation ◽  
Frequency Stimulation

Memory is stored in neural networks via changes in synaptic strength mediated in part by NMDA receptor (NMDAR)-dependent long-term potentiation (LTP). Here we show that a cholecystokinin (CCK)-B receptor (CCKBR) antagonist blocks high-frequency stimulation-induced neocortical LTP, whereas local infusion of CCK induces LTP. CCK−/−mice lacked neocortical LTP and showed deficits in a cue–cue associative learning paradigm; and administration of CCK rescued associative learning deficits. High-frequency stimulation-induced neocortical LTP was completely blocked by either the NMDAR antagonist or the CCKBR antagonist, while application of either NMDA or CCK induced LTP after low-frequency stimulation. In the presence of CCK, LTP was still induced even after blockade of NMDARs. Local application of NMDA induced the release of CCK in the neocortex. These findings suggest that NMDARs control the release of CCK, which enables neocortical LTP and the formation of cue–cue associative memory.

Low-frequency stimulation of the perforant path produces long-term potentiation in the dentate gyrus of unanesthetized rats

1983 ◽  
Vol 61 (10) ◽  
pp. 1156-1161 ◽  
Author(s):  
R. W. Skelton ◽  
J. J. Miller ◽  
A. G. Phillips
Keyword(s):  
Dentate Gyrus ◽  
Low Frequency ◽  
Long Term Potentiation ◽  
Perforant Path ◽  
High Frequency Stimulation ◽  
Synaptic Efficacy ◽  
Term Potentiation ◽  
Frequency Stimulation ◽  
Stimulation Of

Brief periods of high-frequency stimulation of hippocampal afferents produce long-term potentiation (LTP) of synaptic transmission, but the minimum frequency capable of inducing this alteration in synaptic efficacy has not been specified. The present study used the repeated measurement of input–output curves in the perforant path – dentate gyrus system of freely moving rats to monitor synaptic efficacy and found that stimulation at 0.2 Hz, but not 0.04 Hz produced LTP. These results suggest that the minimum stimulation frequency capable of producing LTP is lower than previously described. Possible reasons for the discrepancy between the present and previous findings are discussed, along with the implications of low-frequency potentiation.

scholarly journals A computational model of dopaminergic modulation of hippocampal Schaffer collateral-CA1 long-term plasticity

2021 ◽  
Author(s):  
Joseph Schmalz ◽  
Gautam Kumar
Keyword(s):  
Learning And Memory ◽  
Low Frequency ◽  
Long Term Potentiation ◽  
Schaffer Collateral ◽  
Low Frequency Stimulation ◽  
Term Potentiation ◽  
Frequency Stimulation ◽  
Ca1 Pyramidal Neuron ◽  
Dose Dependent

AbstractDopamine plays a critical role in modulating the long-term synaptic plasticity of the hippocampal Schaffer collateral-CA1 pyramidal neuron synapses (SC-CA1), a widely accepted cellular model of learning and memory. Limited results from hippocampal slice experiments over the last four decades have shown that the timing of the activation of dopamine D1/D5 receptors relative to a high/low-frequency stimulation (HFS/LFS) in SC-CA1 synapses regulates the modulation of HFS/LFS-induced long-term potentiation/depression (LTP/LTD) in these synapses. However, the existing literature lacks a complete picture of how various concentrations of D1/D5 agonists and the relative timing between the activation of D1/D5 receptors and LTP/LTD induction by HFS/LFS, affect the spatiotemporal modulation of SC-CA1 synaptic dynamics. In this paper, we have developed a computational model, a first of its kind, to make quantitative predictions of the temporal dose-dependent modulation of the HFS/LFS induced LTP/LTD in SC-CA1 synapses by D1/D5 agonists activating cAMP-mediating biochemical pathways. Our model combines the biochemical effects with the electrical effects at the electrophysiological level. We have estimated the model parameters from the published electrophysiological data, available from diverse hippocampal CA1 slice experiments, in a Bayesian framework. Our modeling results demonstrate the capability of our model in making quantitative predictions of the available experimental results under diverse HFS/LFS protocols. The predictions from our model show a strong nonlinear dependency of the modulated LTP/LTD by D1/D5 agonists on the relative timing between the activated D1/D5 receptors and the HFS/LFS protocol as well as the applied concentration of D1/D5 agonists. Particularly, our model predicts that D1/D5 agonists could significantly boost the LTP induced by weak HFS if the agonist is applied much before the HFS protocol. Furthermore, our model predicts that specific D1/D5 agonists can convert the LFS-induced LTD in SC-CA1 synapses to LTP if D1/D5 receptors are activated before the applied LFS protocol.Author summaryDopamine, a reward neuromodulator, plays an essential role in shaping hippocampal-dependent learning and memory of behavioral tasks. Limited experimental studies have revealed that pharmacological agents of dopaminergic receptors can significantly modulate the electrically-induced long-term potentiation/depression (LTP/LTD) of the hippocampal Schaffer collateral CA1 pyramidal (SC-CA1) synapses, a cellular model of learning and memory, in a time and dose dependent manner.However, exploring the effect of the parameter space of various concentration levels of the applied pharmacological agent as well as the frequency-specific characteristics of the high (low) frequency stimulation (H(L)FS) protocol on the dopaminergic receptors’ mediated spatiotemporal modulation of LTP/LTD is a combinatorically challenging problem which is both expensive and time-consuming to address in experiments alone. Here, we develop a multi-timescale computational modeling framework to address this question. Our model integrates the slow biochemical dynamics and the fast-electrical dynamics of the CA1 pyramidal neuron and makes quantitative predictions of the experimentally observed modulation of H(L)FS-induced LTP/LTD in SC-CA1 synapses by dopaminergic (D1/D5) receptors agonists. Our modeling results complement the experimental findings and show specific predictions on the potential role of dopamine in strengthening weak synapses.

scholarly journals Etomidate Targets α5γ-Aminobutyric Acid Subtype A Receptors to Regulate Synaptic Plasticity and Memory Blockade

2009 ◽  
Vol 111 (5) ◽  
pp. 1025-1035 ◽  
Author(s):  
Loren J. Martin ◽  
Gabriel H. T. Oh ◽  
Beverley A. Orser
Keyword(s):  
Synaptic Plasticity ◽  
High Frequency ◽  
Memory Performance ◽  
Long Term Potentiation ◽  
Aminobutyric Acid ◽  
High Frequency Stimulation ◽  
Term Potentiation ◽  
Frequency Stimulation ◽  
Subtype A

Background The memory-blocking properties of general anesthetics have recently received considerable attention because of concerns related to intraoperative awareness and postoperative cognitive dysfunction. The goal of this study was to identify the mechanisms by which gamma-aminobutyric acid subtype A receptors that contain the alpha5 subunit (alpha5GABAARs) induce memory-blockade by etomidate and a pharmacologic strategy to reverse this impairment. Methods The effects of etomidate and the alpha5GABAAR-preferring inverse agonist L-655,708 on the plasticity of glutamatergic excitatory transmission in hippocampal slices and behavioral memory for spatial navigational and fear-associated memory tasks were studied in wild-type and null mutant mice for the gene that encodes the alpha5 subunit (Gabra5-/- mice). Long-term potentiation of field excitatory postsynaptic potentials was induced in CA1 pyramidal neurons following high-frequency stimulation of Schaffer collaterals. Memory performance was studied in contextual, cued, and trace fear conditioning assays and the Morris water maze. Results Robust synaptic plasticity induced by high-frequency stimulation and memory performance for contextual fear and spatial navigational memory were not influenced by a decrease in the function of alpha5GABAARs. Nevertheless, etomidate, via an increase in alpha5GABAAR activity, completely blocked long-term potentiation and impaired memory performance, and these effects were reversed by pretreatment with L-655,708. Conclusions The results provide the first proof of concept that memory blockade by a general anesthetic can be reversed by inhibiting the function of alpha5GABAARs. The findings suggest a mechanism and model for awareness during anesthesia.

scholarly journals SCRAPPER Regulates the Thresholds of Long-Term Potentiation/Depression, the Bidirectional Synaptic Plasticity in Hippocampal CA3-CA1 Synapses

2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
Hiroshi Takagi ◽  
Mitsutoshi Setou ◽  
Seiji Ito ◽  
Ikuko Yao
Keyword(s):  
Synaptic Plasticity ◽  
Hippocampal Slices ◽  
Low Frequency ◽  
Long Term Potentiation ◽  
Low Frequency Stimulation ◽  
Term Potentiation ◽  
Hippocampal Ca3 ◽  
Frequency Stimulation ◽  
F Box Protein

SCRAPPER, which is an F-box protein encoded byFBXL20, regulates the frequency of the miniature excitatory synaptic current through the ubiquitination of Rab3-interacting molecule 1. Here, we recorded the induction of long-term potentiation/depression (LTP/LTD) in CA3-CA1 synapses in E3 ubiquitin ligase SCRAPPER-deficient hippocampal slices. Compared to wild-type mice,Scrapper-knockout mice exhibited LTDs with smaller magnitudes after induction with low-frequency stimulation and LTPs with larger magnitudes after induction with tetanus stimulation. These findings suggest that SCRAPPER regulates the threshold of bidirectional synaptic plasticity and, therefore, metaplasticity.

Analyzing synaptic plasticity at the single cell level with STDP

Neuroforum ◽  
2018 ◽  
Vol 24 (3) ◽  
pp. A143-A150
Author(s):  
Elke Edelmann ◽  
Volkmar Leßmann
Keyword(s):  
Synaptic Plasticity ◽  
Molecular Mechanisms ◽  
Brain Slices ◽  
Low Frequency ◽  
Long Term Potentiation ◽  
Spike Timing ◽  
Postsynaptic Neuron ◽  
Action Potential Firing ◽  
Pipette Solution

Abstract Using patch clamp recordings in acutely isolated brain slices allows to investigate molecular processes that are involved in long-term potentiation (LTP) and long-term depression (LTD) at the level of a single postsynaptic neuron. Via the pipette solution in the recording pipette, it is possible to apply inhibitors of signaling cascades selectively into the postsynaptic neuron to unravel the molecular mechanisms of synaptic plasticity. In recent years, LTP research has been increasingly focused on induction protocols for LTP and LTD that rely on a minimal number of repeated synaptic stimulations at low frequency to induce synaptic plasticity. This is where spike timing-dependent plasticity (STDP) comes into play. STDP can be induced by repetitive pairings of action potential firing in presynaptic (first neuron) – and postsynaptic (second synaptically connected) neurons, that occurs with a delay of roughly 5–20 ms in forward or backward manner. While forward pairing with short positive time delays (“pre before post”) leads to LTP, backward pairing (“post before pre”) leads to LTD. In addition to the exact sequence and timing of pre- and postsynaptic spiking, the presence of neuromodulatory transmitters in the extracellular space (e. g., dopamine, acetylcholine, noradrenaline) and the synaptic release of intercellular mediators of synaptic plasticity (e. g., BDNF, endocannabinoids) critically regulate the outcome of STDP protocols. In this review we focus on the role of these mediators and modulators of synaptic plasticity in STDP.

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