Anoxic LTP is mediated by the redox modulatory site of the NMDA receptor

1. The effects of redox reagents, 5,5'-dithiobis-2-nitrobenzoic acid (DTNB) and tris(carboxyethyl)phosphine (TCEP), on anoxia-induced long-term potentiation (LTP) were investigated in CA1 hippocampal neurons using extracellular recording techniques. Experiments were performed in the presence of 0.1 mM MgCl2 and 10 microM 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) to pharmacologically isolate N-methyl-D-aspartate (NMDA) receptor-mediated responses. 2. DTNB (200 microM), a thiol oxidizing reagent, reduces by 52 +/- 9% (mean +/- SE) (n = 9/9) NMDA-receptor field potentials evoked by electrical stimulation of Schaffer collaterals and this effect could not be reversed by extensive washing. Nearly the same reduction of the initial response was obtained with different concentrations of DTNB (100 and 500 microM), but the time required to reach the maximal inhibition was concentration-dependent. 3. In keeping with an earlier study oxygen and glucose deprivation for 2-3 min induced a long-term potentiation (LTP) of the NMDA receptor response (+65 +/- 16%, n = 4/6). This potentiation was reversed by DTNB (100-500 microM) (-47 +/- 18%; n = 4/4) and the initial LTP could not be restored upon extensive washing of the drug. 4. TCEP (200 microM), a reagent which reduces S-S bond, amplified the electrically evoked NMDA-receptor EPSP (+27 +/- 12%; n = 3). In addition, TCEP (200 microM), nearly completely reversed the effect of DTNB (200 microM) on anoxia-induced LTP (+56 +/- 19%; n = 3/3). Preliminary results also indicate that TCEP occlude anoxic-LTP (n = 3/4). 5. Following DTNB (200 microM) treatment, oxygen and glucose deprivation did not generate anoxic LTP and extensive washing did not restore a potentiated NMDA field potential. 6. These observations strongly suggest that the redox site of the NMDA receptor is involved in the induction and the maintenance of the anoxic LTP of the NMDA receptor-mediated response in CA1.

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

Journal of Neurophysiology ◽

10.1152/jn.1995.74.3.1075 ◽

1995 ◽

Vol 74 (3) ◽

pp. 1075-1082 ◽

Cited By ~ 150

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.

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Anoxia-induced LTP of isolated NMDA receptor-mediated synaptic responses

Journal of Neurophysiology ◽

10.1152/jn.1993.69.5.1774 ◽

1993 ◽

Vol 69 (5) ◽

pp. 1774-1778 ◽

Cited By ~ 72

Author(s):

V. Crepel ◽

C. Hammond ◽

K. Krnjevic ◽

P. Chinestra ◽

Y. Ben-Ari

Keyword(s):

Nmda Receptor ◽

Neuronal Death ◽

Hippocampal Neurons ◽

Input Resistance ◽

Long Term Potentiation ◽

Term Potentiation ◽

Bath Application ◽

Synaptic Responses

1. The effects of an anoxic-aglycemic episode (1-3 min) on the pharmacologically isolated N-methyl-D-aspartate (NMDA)-mediated responses were examined in CA1 pyramidal hippocampal neurons in vitro. 2. An anoxic-aglycemic episode induced a long term potentiation (LTP) of the NMDA receptor-mediated field excitatory post-synoptic potentials (EPSPs). This LTP, referred to as anoxic LTP, was observed in the presence of 1) a normal Mg2+ concentration [+40.1 +/- 5% (mean +/- SE)], 2) a low Mg2+ concentration (+52.2 +/- 10%), or 3) a Mg2+ free (+49 +/- 11%), 1 h after anoxia. 3. Bath application of D-2-amino-5-phosphonovaleric acid (D-APV, 20 microM, 15-21 min) before, during, and after the anoxic-aglycemic episode, which transiently blocked the synaptic NMDA receptor mediated response, prevented the induction of anoxic LTP. 4. The intracellularly recorded NMDA receptor-mediated EPSP was also persistently potentiated by anoxia-aglycemia (+47 +/- 4%). This potentiation was not associated with changes in membrane potential or input resistance. 5. These findings provide the first evidence that an anoxic-aglycemic episode induces an LTP of NMDA receptor-mediated responses. This potentiation may participate in the cascade of events that lead to delayed neuronal death.

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Calcium signals in long-term potentiation and long-term depression

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y99-079 ◽

1999 ◽

Vol 77 (9) ◽

pp. 722-734 ◽

Cited By ~ 15

Author(s):

John A Connor ◽

Jeffrey Petrozzino ◽

Lucas D Pozzo-Miller ◽

Satoru Otani

Keyword(s):

Nmda Receptor ◽

Neuronal Plasticity ◽

Hippocampal Neurons ◽

Low Frequency ◽

Long Term Potentiation ◽

Long Term Depression ◽

Metabotropic Receptor ◽

Ca1 Neurons ◽

Term Potentiation

We describe postsynaptic Ca2+ signals that subserve induction of two forms of neuronal plasticity, long-term potentiation (LTP) and long-term depression (LTD), in rat hippocampal neurons. The common induction protocol for LTP, a 1-s, 50-Hz tetanus, generates Ca2+ increases of about 50 µM in dendritic spines of CA1 neurons. These very large increases, measured using a low affinity indicator (Mg fura 5), were found only in the spines and tertiary dendrites, and were dependent upon influx through N-methyl-D-aspartate (NMDA) gated channels. High affinity Ca2+ indicators (e.g., fura 2) are unable to demonstrate these events. In acute slices, neighboring dendritic branches often showed very different responses to a tetanus, and in some instances, neighboring spines on the same dendrite responded differently. LTD in mature CA1 neurons was induced by a low frequency stimulus protocol (2 Hz, 900 pulses), in the presence of GABA- and NMDA-receptor blockers. This LTD protocol produced dendritic Ca2+ increases of <1 µM. Duration of the Ca2+ increase was ~30 s and was due to voltage-gated Ca2+ influx. Finally, the ability of synaptically addressed Ca2+ stores to release Ca2+ was studied in CA3 neurons and was found to require immediate preloading and high intensity presynaptic stimulation, conditions unlike normal LTP-LTD protocols.Key words: long-term potentiation, long-term depression, Ca2+, neuronal plasticity, fluorescence imaging, N-methyl-D-aspartate (NMDA) receptor, metabotropic receptor.

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Activation of the NMDA receptor: a correlate in the dentate gyrus field potential and its relationship to long-term potentiation and kindling

Brain Research ◽

10.1016/0006-8993(91)90310-r ◽

1991 ◽

Vol 556 (2) ◽

pp. 226-239 ◽

Cited By ~ 20

Author(s):

R.J. Racine ◽

K.-A. Moore ◽

S. Wicks

Keyword(s):

Nmda Receptor ◽

Dentate Gyrus ◽

Field Potential ◽

Long Term Potentiation ◽

Term Potentiation

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Sensitivity of Synaptic Plasticity to the Ca2+ Permeability of NMDA Channels: A Model of Long-Term Potentiation in Hippocampal Neurons

Neural Computation ◽

10.1162/neco.1993.5.5.681 ◽

1993 ◽

Vol 5 (5) ◽

pp. 681-694 ◽

Cited By ~ 3

Author(s):

Erik De Schutter ◽

James M. Bower

Keyword(s):

Nmda Receptor ◽

Dendritic Spines ◽

Hippocampal Neurons ◽

Dendritic Tree ◽

Long Term Potentiation ◽

Synaptic Activation ◽

Term Potentiation ◽

Nmda Channels ◽

Maximum Amplification

We have examined a model by Holmes and Levy (1990) of the induction of associative long-term potentiation (LTP) by a rise in the free Ca2+ concentration ([Ca2+]) after synaptic activation of dendritic spines. The previously reported amplification of the change in [Ca2+] caused by coactivation of several synapses was found to be quite sensitive to changes in the permeability of the N-methyl-D-aspartate (NMDA) receptor channels to Ca2+. Varying this parameter indicated that maximum amplification is obtained at values that are close to Ca2+ permeabilities reported in the literature. However, amplification failed if permeability is reduced by more than 50%. We also found that the maximum free [Ca2+] reached in an individual spine during synaptic coactivation of several spines depended on the location of that spine on the dendritic tree. Distal spines attained a higher [Ca2+] than proximal ones, with differences of up to 80%. The implications of this result for the uniformity of induction of associative LTP in spines in different regions of the dendrite are discussed.

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A selective LTP of NMDA receptor-mediated currents induced by anoxia in CA1 hippocampal neurons

Journal of Neurophysiology ◽

10.1152/jn.1993.70.5.2045 ◽

1993 ◽

Vol 70 (5) ◽

pp. 2045-2055 ◽

Cited By ~ 98

Author(s):

V. Crepel ◽

C. Hammond ◽

P. Chinestra ◽

D. Diabira ◽

Y. Ben-Ari

Keyword(s):

Nmda Receptor ◽

Ampa Receptor ◽

Ampa Receptors ◽

Hippocampal Neurons ◽

Long Term Potentiation ◽

Peak Amplitude ◽

Excitatory Postsynaptic Potential ◽

Physiological Concentration ◽

Term Potentiation

1. The possibility of long-lasting modifications of glutamatergic responses after anoxic-aglycemic (AA) episodes was investigated in CA1 hippocampal neurons of adult slices. Bicuculline (10 microM) was continuously bath applied to block GABAA receptor-mediated currents. AA episodes were induced by brief (1.30-3 min) perfusions with a glucose free artificial-cerebro-spinal-fluid (ACSF) saturated with 95% N2-5% CO2. 2. In presence of (0.6 mM) Mg2+ and a low concentration of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 1 microM), the Schaffer collateral field EPSPs consisted of an early AMPA receptor-mediated component and a late N-methyl-D-aspartate (NMDA) receptor-mediated component. The former was blocked by (10 microM) CNQX and the latter by (50) microM D-2-amino-5-phosphonovalerate (D-APV). The AA episode induced a selective long-term potentiation (LTP) of the NMDA receptor-mediated component [+70 +/- 13% (mean +/- SE), P < or = 0.008, n = 9] without affecting significantly the AMPA receptor-mediated component (+2 +/- 4, P < or = 0.86 n = 9). This selective LTP is due to an enhanced efficacy of synaptic transmission and will be referred to as anoxic LTP. 3. In slices perfused with an ACSF containing a physiological concentration of (1.3 mM) Mg2+ and no CNQX, the intracellularly recorded excitatory postsynaptic potential (EPSP) was mixed (AMPA/NMDA) at -65 mV and exclusively mediated by AMPA receptors at -100 mV. At -65 mV, the AA episode induced a persistent potentiation of the EPSP (peak amplitude potentiated by 43 +/- 6%, P < or = 0.008, n = 9, 1 h after return to control ACSF). This potentiated component of the EPSP was fully sensitive to (50 microM) D-APV. The CNQX-sensitive AMPA receptor-mediated component was not affected by the AA episode (-5.7 +/- 6%, P < or = 0.123, n = 9). Furthermore, at -100 mV a large APV-sensitive component appeared after the AA episode (+58 +/- 18% of the peak amplitude, P < or = 0.018, n = 9). Therefore, the AA episode induced a selective LTP of the NMDA receptor-mediated component of the EPSP. 4. A robust LTP (+50.0 +/- 7.5%, P < or = 0.008, n = 12) of the NMDA receptor-mediated intracellular EPSP was also observed when AMPA receptors were fully and continuously blocked by (15 microM) CNQX.(ABSTRACT TRUNCATED AT 400 WORDS)

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