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

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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Chemical LTD, but not LTP, induces transient accumulation of gelsolin in dendritic spines

Biological Chemistry ◽

10.1515/hsz-2019-0110 ◽

2019 ◽

Vol 400 (9) ◽

pp. 1129-1139 ◽

Cited By ~ 2

Author(s):

Iryna Hlushchenko ◽

Pirta Hotulainen

Keyword(s):

Synaptic Plasticity ◽

Dendritic Spines ◽

Hippocampal Neurons ◽

Long Term Potentiation ◽

Excitatory Synapses ◽

Signal Molecule ◽

Brain Functions ◽

Dendritic Shaft ◽

Term Potentiation

Abstract Synaptic plasticity underlies central brain functions, such as learning. Ca2+ signaling is involved in both strengthening and weakening of synapses, but it is still unclear how one signal molecule can induce two opposite outcomes. By identifying molecules, which can distinguish between signaling leading to weakening or strengthening, we can improve our understanding of how synaptic plasticity is regulated. Here, we tested gelsolin’s response to the induction of chemical long-term potentiation (cLTP) or long-term depression (cLTD) in cultured rat hippocampal neurons. We show that gelsolin relocates from the dendritic shaft to dendritic spines upon cLTD induction while it did not show any relocalization upon cLTP induction. Dendritic spines are small actin-rich protrusions on dendrites, where LTD/LTP-responsive excitatory synapses are located. We propose that the LTD-induced modest – but relatively long-lasting – elevation of Ca2+ concentration increases the affinity of gelsolin to F-actin. As F-actin is enriched in dendritic spines, it is probable that increased affinity to F-actin induces the relocalization of gelsolin.

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

Journal of Neurophysiology ◽

10.1152/jn.1994.72.6.3017 ◽

1994 ◽

Vol 72 (6) ◽

pp. 3017-3022 ◽

Cited By ~ 42

Author(s):

H. Gozlan ◽

D. Diabira ◽

P. Chinestra ◽

Y. Ben-Ari

Keyword(s):

Nmda Receptor ◽

Hippocampal Neurons ◽

Field Potential ◽

Extracellular Recording ◽

Glucose Deprivation ◽

Long Term Potentiation ◽

Receptor Field ◽

Oxygen And Glucose Deprivation ◽

Term Potentiation

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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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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NMDA receptor-dependent long-term potentiation comprises a family of temporally overlapping forms of synaptic plasticity that are induced by different patterns of stimulation

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2013.0131 ◽

2014 ◽

Vol 369 (1633) ◽

pp. 20130131 ◽

Cited By ~ 66

Author(s):

Pojeong Park ◽

Arturas Volianskis ◽

Thomas M. Sanderson ◽

Zuner A. Bortolotto ◽

David E. Jane ◽

...

Keyword(s):

Synaptic Plasticity ◽

Nmda Receptor ◽

Recent Work ◽

Molecular Mechanisms ◽

Long Term Potentiation ◽

Extensive Literature ◽

Synaptic Activation ◽

Aspartate Receptor ◽

Term Potentiation

N -methyl- d -aspartate receptor (NMDAR)-dependent long-term potentiation (LTP) is extensively studied since it is believed to use the same molecular mechanisms that are required for many forms of learning and memory. Unfortunately, many controversies exist, not least the seemingly simple issue concerning the locus of expression of LTP. Here, we review our recent work and some of the extensive literature on this topic and present new data that collectively suggest that LTP can be explained, during its first few hours, by the coexistence of at least three mechanistically distinct processes that are all triggered by the synaptic activation of NMDARs.

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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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