Reversible Synaptic Depression in Developing Rat CA3–CA1 Synapses Explained by a Novel Cycle of AMPA Silencing-Unsilencing

2007 ◽  
Vol 98 (5) ◽  
pp. 2604-2611 ◽  
Author(s):  
Therése Abrahamsson ◽  
Bengt Gustafsson ◽  
Eric Hanse
Keyword(s):  
Metabotropic Glutamate Receptor ◽  
Low Frequency ◽  
Long Term Potentiation ◽  
Synaptic Depression ◽  
Receptor Activation ◽  
Excitatory Postsynaptic Potential ◽  
Whole Cell ◽  
Metabotropic Glutamate ◽  
Silent Synapses ◽  
Recording Conditions

In the developing hippocampus, experiments using whole cell recordings have shown that a small number of synaptic activations can convert many glutamate synapses to AMPA silent synapses. This depression of AMPA signaling is induced by low-frequency (0.05–0.2 Hz) activation, does not require N-methyl-d-aspartate or metabotropic glutamate receptor activation for its induction, and does not readily reverse after stimulus interruption. Here we show, using field recordings and perforated patch-clamp recordings of transmission in developing CA3–CA1 synapses, that this synaptic depression also can be observed under more noninvasive recording conditions. Moreover, under these conditions, the synaptic depression spontaneously recovers within 20 min by the absence of synaptic activation alone, with a time constant of ∼7 min as determined by field excitatory postsynaptic potential recordings. Thus as for the expression of long-term potentiation (LTP), recovery from this depression is susceptible to whole cell dialysis (“wash-out”). In contrast to LTP-induced unsilencing, the AMPA signaling after stimulus interruption was again labile, resumed stimulation resulted in renewed depression. The present study has thus identified a novel cycle for AMPA signaling in which the nascent glutamate synapse cycles between an AMPA silent state, induced by a small number of synaptic activations, and a labile AMPA signaling, induced by prolonged inactivity.

scholarly journals NMDA Receptor-Dependent Metaplasticity by High-Frequency Magnetic Stimulation

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Tursonjan Tokay ◽  
Timo Kirschstein ◽  
Marco Rohde ◽  
Volker Zschorlich ◽  
Rüdiger Köhling
Keyword(s):  
Nmda Receptor ◽  
High Frequency ◽  
Magnetic Stimulation ◽  
Metabotropic Glutamate Receptor ◽  
Hippocampal Slices ◽  
Long Term Potentiation ◽  
Receptor Activation ◽  
Excitatory Postsynaptic Potential ◽  
Metabotropic Glutamate

High-frequency magnetic stimulation (HFMS) can elicit N-methyl-D-aspartate (NMDA) receptor-dependent long-term potentiation (LTP) at Schaffer collateral-CA1 pyramidal cell synapses. Here, we investigated the priming effect of HFMS on the subsequent magnitude of electrically induced LTP in the CA1 region of rat hippocampal slices using field excitatory postsynaptic potential (fEPSP) recordings. In control slices, electrical high-frequency conditioning stimulation (CS) could reliably induce LTP. In contrast, the same CS protocol resulted in long-term depression when HFMS was delivered to the slice 30 min prior to the electrical stimulation. HFMS-priming was diminished when applied in the presence of the metabotropic glutamate receptor antagonists (RS)-α-methylserine-O-phosphate (MSOP) and (RS)-α-methyl-4-carboxyphenylglycine (MCPG). Moreover, when HFMS was delivered in the presence of the NMDA receptor-antagonist D-2-amino-5-phosphonovalerate (50 µM), CS-induced electrical LTP was again as high as under control conditions in slices without priming. These results demonstrate that HFMS significantly reduced the propensity of subsequent electrical LTP and show that both metabotropic glutamate and NMDA receptor activation were involved in this form of HFMS-induced metaplasticity.

Modulation of Low-Frequency-Induced Synaptic Depression in the Developing CA3–CA1 Hippocampal Synapses by NMDA and Metabotropic Glutamate Receptor Activation

2009 ◽  
Vol 101 (5) ◽  
pp. 2252-2262 ◽  
Author(s):  
Joakim Strandberg ◽  
Pontus Wasling ◽  
Bengt Gustafsson
Keyword(s):  
Metabotropic Glutamate Receptors ◽  
Metabotropic Glutamate Receptor ◽  
Hippocampal Slices ◽  
Low Frequency ◽  
Synaptic Depression ◽  
Receptor Activation ◽  
Test Pulse ◽  
Metabotropic Glutamate ◽  
Hippocampal Ca3 ◽  
Pulse Stimulation

Brief test-pulse stimulation (0.2–0.05 Hz) of naïve (previously nonstimulated) developing hippocampal CA3–CA1 synapses leads to a substantial synaptic depression, explained by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) silencing. Using field recordings in hippocampal slices from P8 to P12 rats, we examined this depression of naïve synapses using more prolonged test-pulse stimulation as well as low-frequency (1 Hz) stimulation (LFS). We found that 900 stimuli produced depression during stimulation to ∼40% of the naïve level independent of whether test-pulse stimulation or LFS was used. This result was also observed during combined blockade of N-methyl-d-aspartate/metabotropic glutamate receptors (NMDAR/mGluRs) although the depression was smaller (to ∼55% of naïve level). Using separate blockade of either NMDARs or mGluRs, we found that this impairment of the depression resulted from the NMDAR, and not from the mGluR, blockade. In fact, during NMDAR blockade alone, depression was smaller even than that observed during combined blockade. We also found that mGluR blockade alone facilitated the LFS-induced depression. In conclusion, test-pulse stimulation produced as much depression as LFS when applied to naïve synapses even when allowing for NMDAR and mGluR activation. Our results seem in line with the notion that NMDARs and mGluRs may exert a bidirectional control on AMPA receptor recruitment to synapses.

Reexamination of the effects of MCPG on hippocampal LTP, LTD, and depotentiation

1995 ◽  
Vol 74 (3) ◽  
pp. 1075-1082 ◽  
Author(s):  
D. K. Selig ◽  
H. K. Lee ◽  
M. F. Bear ◽  
R. C. Malenka
Keyword(s):  
Hippocampal Neurons ◽  
Metabotropic Glutamate Receptor ◽  
Low Frequency ◽  
Extracellular Recording ◽  
Pyramidal Cells ◽  
Long Term Potentiation ◽  
Metabotropic Glutamate ◽  
Term Potentiation ◽  
Frequency Stimulation

1. We examined the effects of the metabotropic glutamate receptor (mGluR) antagonist alpha-methyl-4-carboxyphenylglycine (MCPG) on the induction of long-term potentiation (LTP) long-term depression (LTD), and depotentiation in CA1 hippocampal neurons using extracellular recording techniques. 2. MCPG (500 microM) strongly antagonized the presynaptic inhibitory action of the mGluR agonist 1-aminocyclopentane-(1S,3R)-dicarboxylic acid yet failed to block LTP induced with either tetanic stimulation (100 Hz, 1 s) or theta-burst stimulation. 3. To test the possibility that our failure to block LTP was due to prior activation of a "molecular switch" that in its "on" state obviates the need for mGluR activation to generate LTP, we gave repeated periods of prolonged low-frequency stimulation (LFS; 1 Hz, 10 min), a manipulation reported to turn the switch "off." Although this stimulation saturated LTD, subsequent application of MCPG still failed to block LTP. 4. MCPG did not block LFS-induced depotentiation in older slices (4-6 wk) or LFS-induced LTD in older, young (11-18 days), or neonatal (3-7 days) slices. 5. These results demonstrate that MCPG-sensitive mGluRs are not necessary for the induction of LTP, LTD, or depotentiation in hippocampal CA1 pyramidal cells. The possibility remains, however, that their activation may modify the threshold for the induction of these long-term plastic changes.

Dynamics of Excitatory Synaptic Components in Sustained Firing at Low Rates

2005 ◽  
Vol 93 (6) ◽  
pp. 3370-3380 ◽  
Author(s):  
Claire Wyart ◽  
Simona Cocco ◽  
Laurent Bourdieu ◽  
Jean-Francois Léger ◽  
Catherine Herr ◽  
...  
Keyword(s):  
Metabotropic Glutamate Receptor ◽  
Temporal Dynamics ◽  
Low Frequency ◽  
Firing Frequency ◽  
Excitatory Postsynaptic Potential ◽  
Metabotropic Glutamate ◽  
Wide Range ◽  
Nmdar Activation ◽  
Asynchronous Release ◽  
Low Rate

Sustained firing is necessary for the persistent activity associated with working memory. The relative contributions of the reverberation of excitation and of the temporal dynamics of the excitatory postsynaptic potential (EPSP) to the maintenance of activity are difficult to evaluate in classical preparations. We used simplified models of synchronous excitatory networks, hippocampal autapses and pairs, to study the synaptic mechanisms underlying firing at low rates. Calcium imaging and cell attached recordings showed that these neurons spontaneously fired bursts of action potentials that lasted for seconds over a wide range of frequencies. In 2-wk-old cells, the median firing frequency was low (11 ± 8.8 Hz), whereas in 3- to 4-wk-old cells, it decreased to a very low value (2 ± 1.3 Hz). In both cases, we have shown that the slowest synaptic component supported firing. In 2-wk-old autapses, antagonists of N-methyl-d-aspartate receptors (NMDARs) induced rare isolated spikes showing that the NMDA component of the EPSP was essential for bursts at low frequency. In 3- to 4-wk-old neurons, the very low frequency firing was maintained without the NMDAR activation. However EGTA-AM or α-methyl-4-carboxyphenylglycine (MCPG) removed the very slow depolarizing component of the EPSP and prevented the sustained firing at very low rate. A metabotropic glutamate receptor (mGluR)-activated calcium sensitive conductance is therefore responsible for a very slow synaptic component associated with firing at very low rate. In addition, our observations suggested that the asynchronous release of glutamate might participate also in the recurring bursting.

Metabotropic glutamate receptor-mediated presynaptic depression at corticostriatal synapses involves mGLuR2 or 3

1995 ◽  
Vol 73 (3) ◽  
pp. 1076-1083 ◽  
Author(s):  
D. M. Lovinger ◽  
B. A. McCool
Keyword(s):  
Glutamate Receptor ◽  
Metabotropic Glutamate Receptor ◽  
Field Potential ◽  
Receptor Activation ◽  
Striatal Neurons ◽  
Afferent Stimulation ◽  
Striatal Slices ◽  
Whole Cell ◽  
Metabotropic Glutamate ◽  
Whole Cell Recordings

1. The pharmacology of the metabotropic glutamate receptor (mGluR) that mediates synaptic depression at corticostriatal synapses was investigated with the use of field potential and whole cell patch-clamp recording from striatal slices and whole cell recordings from isolated striatal neurons. 2. The mGluR2,3-selective agonists (R,S)-4-carboxy-3-hydroxyphenylglycine (CHPG), (2S, 1'R,2'R,3'R)-2-(2,3-dicarboxycyclopropyl) glycine (DCG-IV), and (2S, 3S, 4S)-alpha-(carboxycyclopropyl) glycine (L-CCG-I) inhibited the synaptically driven population spike (PS) evoked by afferent stimulation during field potential recording in striatal slices. These agonists also inhibited excitatory postsynaptic potentials (EPSPs) evoked by afferent stimulation during whole cell recordings. The metabotropic receptor antagonist R,S-alpha-methyl-4-carboxyphenylglycine (MCPG) blocked the synaptic depressant actions of DCG-IV and trans-1-aminocyclopentane-1,3-dicarboxylic acid (t-ACPD). 3. The mGluR4,6,7-selective agonist L-serine-O-phosphate (L-SOP) did not alter corticostriatal synaptic transmission, but both this agonist and the mGluR4,6,7 agonist D,L-2-amino-4-phosphonobutyric acid (AP4) reduced the amplitude of the population EPSP and PS evoked in the dentate gyrus (DG) by stimulation of the lateral perforant path (LPP). These data are consistent with earlier observations that AP4 does not inhibit corticostriatal transmission, but produces presynaptic depression at LPP-DG synapses. 4. Application of mGluR agonists that inhibited transmission did not alter the input resistance or excitability of striatal neurons and did not inhibit responses evoked by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptor activation.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Selective Abolition of the NMDA Component of Long-Term Potentiation in Mice Lacking mGluR5

1998 ◽  
Vol 5 (4) ◽  
pp. 331-343
Author(s):  
Zhengping Jia ◽  
YouMing Lu ◽  
Jeff Henderson ◽  
Franco Taverna ◽  
Carmelo Romano ◽  
...  
Keyword(s):  
Nmda Receptor ◽  
Nmda Receptors ◽  
Metabotropic Glutamate Receptors ◽  
Metabotropic Glutamate Receptor ◽  
Long Term Potentiation ◽  
Mutant Mice ◽  
Excitatory Postsynaptic Potential ◽  
Metabotropic Glutamate ◽  
Term Potentiation

The mechanisms underlying the differential expression of long-term potentiation (LTP) by AMPA and NMDA receptors, are unknown, but could involve G-protein-linked metabotropic glutamate receptors. To investigate this hypothesis we created mutant mice that expressed no metabotropic glutamate receptor 5 (mGluR5), but showed normal development. In an earlier study of these mice we analyzed field-excitatory postsynaptic potential (fEPSPs) in CA1 region of the hippocampus and found a small decrease; possibly arising from changes in the NMDAR-mediated component of synaptic transmission. In the present study we used whole-cell patch clamp recordings of evoked excitatory postsynaptic currents (EPSCs) in CA1 pyramidal neurons to identify the AMPAR- and NMDAR-mediated components of LTP. Recordings from control mice following tetanus, or agonist application (IS, 3R-1-amino-cyclopentane 1,3-dicarboxylic acid) (ACPD), revealed equal enhancement of the AMPA and NMDA receptor-mediated components. In contrast, CA1 neurons from mGluR5-deficient mice showed a complete loss of the NMDA-receptor-mediated component of LTP (LTPNMDA), but normal LTP of the AMPA-receptor-mediated component (LTPAMPA). This selective loss of LTPNMDA was seen in three different genotypic backgrounds and was apparent at all holding potentials (−70 mV to +20 mV). Furthermore, the LTPNMDA deficit in mGluR5 mutant mice could be rescued by stimulating protein kinase C (PKC) with 4β-phorbol-12,13-dibutyrate (PDBu). These results suggest that PKC may couple the postsynaptic mGluR5 to the NMDA-receptor potentiation during LTP, and that this signaling mechanism is distinct from LTPAMPA. Differential enhancement of AMPAR and NMDA receptors by mGluR5 also supports a postsynaptic locus for LTP.

NMDA-Independent LTP by Adenosine A2 Receptor-Mediated Postsynaptic AMPA Potentiation in Hippocampus

1997 ◽  
Vol 78 (4) ◽  
pp. 1965-1972 ◽  
Author(s):  
Kofi Kessey ◽  
David J. Mogul
Keyword(s):  
Synaptic Transmission ◽  
Ampa Receptor ◽  
Hippocampal Slices ◽  
Low Frequency ◽  
Long Term Potentiation ◽  
Receptor Activation ◽  
Common Mechanism ◽  
Excitatory Postsynaptic Potential ◽  
Ca1 Region ◽  
The Brain

Kessey, Kofi and David J. Mogul. NMDA-independent LTP by adenosine A2 receptor-mediated postsynaptic AMPA potentiation in hippocampus. J. Neurophysiol. 78: 1965–1972, 1997. The role of adenosine A2 receptors in normal synaptic transmission and tetanus-induced long-term potentiation (LTP) was tested by stimulation of the Schaffer collateral pathway and recording of the field excitatory postsynaptic potential (EPSP) in the CA1 region of rat transverse hippocampal slices. Activation of adenosine A2 receptors with the A2 agonist N 6-[2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)-ethyl]adenosine (DPMA; 20 nM) enhanced synaptic transmission during low-frequency test pulses (0.033 Hz). Paired stimulation before and during DPMA exposure indicated no paired-pulse facilitation as a result of A2 activation, suggesting that enhancement was not a result of presynaptic modulation. DPMA enhanced the early phase α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) component of the EPSP. In contrast, DPMA had no effect on the N-methyl-d-aspartate (NMDA) component isolated using low extracellular Mg2+ and the AMPA receptor blocker 6-cyano-7-nitroquinoxaline-2,3-dione (20 μM), indicating that the effects of A2 activation on synaptic transmission were mediated by a postsynaptic enhancement of the AMPA response. Activation of adenosine A2 receptors during a brief tetanus (100 Hz, 1 s) increased the level of LTP by 36% over that seen in response to a tetanus under control conditions. DPMA exposure after prior induction of LTP showed no additional potentiation, indicating that the mechanisms that contribute to both types of increases in synaptic transmission share a common mechanism. A slow onset NMDA-independent LTP could be induced by application of a tetanus during perfusion of DPMA with the NMDA blocker AP5 (50 μM). Blockade of L-type Ca channels with nifedipine (10 μM) had no effect on normal synaptic transmission but reduced NMDA-independent LTP by 32%. Very little NMDA-independent LTP could be induced after prior saturation of NMDA-dependent LTP via multiple tetani spaced 10 min apart, indicating that both forms of LTP are eventually convergent on a common mechanism, presumably the postsynaptic AMPA receptor response. Because extracellular adenosine levels are modulated by cellular activity throughout the brain and because adenosine receptor activation can markedly alter levels of synaptic transmission independent of NMDA receptors, adenosine may play an important and complex role as a modulator of synaptic transmission in the brain.

Metabotropic Glutamate Receptor Activation Modulates Sound Level Processing in the Cochlear Nucleus

1998 ◽  
Vol 80 (1) ◽  
pp. 209-217 ◽  
Author(s):  
Dan H. Sanes ◽  
JoAnn McGee ◽  
Edward J. Walsh
Keyword(s):  
Glutamate Receptors ◽  
Glutamate Receptor ◽  
Cochlear Nucleus ◽  
Metabotropic Glutamate Receptors ◽  
Metabotropic Glutamate Receptor ◽  
Long Term Potentiation ◽  
Receptor Activation ◽  
Sound Level ◽  
Metabotropic Glutamate

Sanes, Dan H., JoAnn McGee, and Edward J. Walsh. Metabotropic glutamate receptor activation modulates sound level processing in the cochlear nucleus. J. Neurophysiol. 80: 209–217, 1998. The principal role of ionotropic glutamate receptors in the transmission and processing of information in the auditory pathway has been investigated extensively. In contrast, little is known about the functional contribution of the G-protein–coupled metabotropic glutamate receptors (mGluRs), although their anatomic location suggests that they exercise a significant influence on auditory processing. To investigate this issue, sound-evoked responses were obtained from single auditory neurons in the cochlear nuclear complex of anesthetized cats and gerbils, and metabotropic ligands were administered locally through microionophoretic pipettes. In general, microionophoresis of the mGluR agonists, (1 S,3 R)-1-aminocyclopentane-1,3-dicarboxylic acid or (2 S,1′ S,2′ S)-2-(carboxycyclopropyl)glycine, initially produced a gradual increase in spontaneous and sound-evoked discharge rates. However, activation and recovery times were significantly longer than those observed for ionotropic agonists, such as N-methyl-d-aspartate or α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, consistent with the recruitment of a second-messenger system. The efficacy of mGluR agonists was diminished after administration of the mGluR antagonist, (+)-α-methyl-4-carboxyphenylglycine, consistent with a selective action at metabotropic recognition sites. In contrast, two distinct changes were observed after the mGluR agonist had been discontinued for several minutes. Approximately 50% of neurons exhibited a chronic depression of sound-evoked discharge rate reminiscent of long-term depression, a cellular property observed in other systems. Approximately 30% of neurons exhibited a long-lasting enhancement of the sound-evoked response similar to the cellular phenomenon of long-term potentiation. These findings suggest that mGluR activation has a profound influence on the gain of primary afferent driven activity in the caudal cochlear nucleus.

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