On the Respective Roles of Nitric Oxide and Carbon Monoxide in Long-Term Potentiation in the Hippocampus

Perfusion of hippocampal slices with an inhibitor of nitric oxide (NO) synthase-blocked induction of long-term potentiation (LTP) produced by a one-train tetanus and significantly reduced LTP by a two-train tetanus, but only slightly reduced LTP by a four-train tetanus. Inhibitors of heme oxygenase, the synthetic enzyme for carbon monoxide (CO), significantly reduced LTP by either a two-train or four-train tetanus. These results suggest that NO and CO are both involved in LTP but may play somewhat different roles. One possibility is that NO serves a phasic, signaling role, whereas CO provides tonic, background stimulation. Another possibility is that NO and CO are phasically activated under somewhat different circumstances, perhaps involving different receptors and second messengers. Because NO is known to be activated by stimulation of NMDA receptors during tetanus, we investigated the possibility that CO might be activated by stimulation of metabotropic glutamate receptors (mGluRs). Consistent with this idea, long-lasting potentiation by the mGluR agonist tACPD was blocked by inhibitors of heme oxygenase but not NO synthase. Potentiation by tACPD was also blocked by inhibitors of soluble guanylyl cyclase (a target of both NO and CO) or cGMP-dependent protein kinase, and guanylyl cyclase was activated by tACPD in hippocampal slices. However, biochemical assays indicate that whereas heme oxygenase is constitutively active in hippocampus, it does not appear to be stimulated by either tetanus or tACPD. These results are most consistent with the possibility that constitutive (tonic) rather than stimulated (phasic) heme oxygenase activity is necessary for potentiation by tetanus or tACPD, and suggest that mGluR activation stimulates guanylyl cyclase phasically through some other pathway.

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On the Respective Roles of Nitric Oxide and Carbon Monoxide in Long-Term Potentiation in the Hippocampus

Learning & Memory ◽

10.1101/lm.6.1.63 ◽

1999 ◽

Vol 6 (1) ◽

pp. 63-76 ◽

Cited By ~ 1

Author(s):

Min Zhuo ◽

Jarmo T. Laitinen ◽

Xiao-Ching Li ◽

Robert D. Hawkins

Keyword(s):

Nitric Oxide ◽

Carbon Monoxide ◽

Heme Oxygenase ◽

Guanylyl Cyclase ◽

Hippocampal Slices ◽

Long Term Potentiation ◽

No Synthase ◽

Term Potentiation ◽

Stimulation Of

Perfusion of hippocampal slices with an inhibitor nitric oxide (NO) synthase blocked induction of long-term potentiation (LTP) produced by a one-train tetanus and significantly reduced LTP by a two-train tetanus, but only slightly reduced LTP by a four-train tetanus. Inhibitors of heme oxygenase, the synthetic enzyme for carbon monoxide (CO), significantly reduced LTP by either a two-train or four-train tetanus. These results suggest that NO and CO are both involved in LTP but may play somewhat different roles. One possibility is that NO serves a phasic, signaling role, whereas CO provides tonic, background stimulation. Another possibility is that NO and CO are phasically activated under somewhat different circumstances, perhaps involving different receptors and second messengers. Because NO is known to be activated by stimulation of NMDA receptors during tetanus, we investigated the possibility that CO might be activated by stimulation of metabotropic glutamate receptors (mGluRs). Consistent with this idea, long-lasting potentiation by the mGluR agonist tACPD was blocked by inhibitors of heme oxygenase but not NO synthase. Potentiation by tACPD was also blocked by inhibitors of soluble guanylyl cyclase (a target of both NO and CO) or cGMP-dependent protein kinase, and guanylyl cyclase was activated by tACPD in hippocampal slices. However, biochemical assays indicate that whereas heme oxygenase is constitutively active in hippocampus, it does not appear to be stimulated by either tetanus or tACPD. These results are most consistent with the possibility that constitutive (tonic) rather than stimulated (phasic) heme oxygenase activity is necessary for potentiation by tetanus or tACPD, and suggest that mGluR activation stimulates guanylyl cyclase phasically through some other pathway.

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Nitric oxide inhibitors facilitate the induction of hippocampal long-term potentiation by modulating NMDA responses

Journal of Neurophysiology ◽

10.1152/jn.1993.70.3.1260 ◽

1993 ◽

Vol 70 (3) ◽

pp. 1260-1263 ◽

Cited By ~ 41

Author(s):

K. Kato ◽

C. F. Zorumski

Keyword(s):

Nitric Oxide ◽

Hippocampal Slices ◽

Long Term Potentiation ◽

No Synthase ◽

Hippocampal Region ◽

Ca1 Region ◽

Term Potentiation ◽

Nitric Oxide Inhibitors ◽

Synthase Inhibitor

1. The effects of the competitive nitric oxide (NO) synthase inhibitor, L-nitroarginine (L-NOArg), on synaptically activated N-methyl-D-aspartate (NMDA) currents and the induction of long-term potentiation (LTP) were studied in the CA1 region of rat hippocampal slices. 2. Application of 10 microM L-NOArg increased the amplitude of NMDA currents by approximately 50% in the presence of 2 mM extracellular Mg2+. This augmentation occurred within minutes of L-NOArg administration and was readily reversible on removal of the drug. L-arginine (100 microM) overcame the enhancement produced by L-NOArg. 3. At 5-100 microM, 10-25-min applications of L-NOArg facilitated the induction of LTP produced by a single 100 Hz X 300 ms tetanus. In control slices, the 100 Hz X 300 ms tetanus was insufficient to induce LTP. The development of LTP in L-NOArg-treated slices was inhibited by 50 microM D-2-amino-5-phosphonovalerate (D-APV), and the effects of L-NOArg were overcome by 10-fold higher concentrations of L-arginine but not by D-arginine. 4. Hemoglobin, an agent that binds NO extracellularly, also facilitated NMDA currents and the development of LTP when administered at 10 microM. 5. These results suggest that tonically released NO modulates the threshold for LTP in the CA1 hippocampal region and are consistent with prior studies indicating that untimely activation of NMDA receptors and release of NO inhibit LTP.

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Enhancement of Long-Term Potentiation by a Potent Nitric Oxide-Guanylyl Cyclase Activator, 3-(5-Hydroxymethyl-2-furyl)-1-benzyl-indazole

Molecular Pharmacology ◽

10.1124/mol.63.6.1322 ◽

2003 ◽

Vol 63 (6) ◽

pp. 1322-1328 ◽

Cited By ~ 53

Author(s):

Wei-Lin Chien ◽

Keng-Chen Liang ◽

Che-Ming Teng ◽

Sheng-Chu Kuo ◽

Fang-Yu Lee ◽

...

Keyword(s):

Nitric Oxide ◽

Guanylyl Cyclase ◽

Long Term Potentiation ◽

Term Potentiation ◽

Cyclase Activator

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Reversal of long-term potentiation (depotentiation) induced by tetanus stimulation of the input to CA1 neurons of guinea pig hippocampal slices

Brain Research ◽

10.1016/0006-8993(91)90867-u ◽

1991 ◽

Vol 555 (1) ◽

pp. 112-122 ◽

Cited By ~ 253

Author(s):

Satoshi Fujii ◽

Kazuo Saito ◽

Hiroyoshi Miyakawa ◽

Ken-ichi Ito ◽

Hiroshi Kato

Keyword(s):

Guinea Pig ◽

Hippocampal Slices ◽

Long Term Potentiation ◽

Ca1 Neurons ◽

Term Potentiation ◽

Stimulation Of

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The nitric oxide synthase inhibitor, N-monomethyl-L-arginine blocks induction of a long-term potentiation-like phenomenon in rat medial frontal cortical neurons in vitro

Journal of Neurophysiology ◽

10.1152/jn.1993.70.3.1255 ◽

1993 ◽

Vol 70 (3) ◽

pp. 1255-1259 ◽

Cited By ~ 40

Author(s):

A. V. Nowicky ◽

L. J. Bindman

Keyword(s):

Nitric Oxide ◽

Cortical Neurons ◽

Long Term Potentiation ◽

Control Group ◽

Term Potentiation ◽

The Mean ◽

Synthase Inhibitor ◽

Stimulation Of

1. Nitric oxide has been implicated in the production of long-term depression (LTD) in the cerebellum and in the production of long-term potentiation (LTP) and LTD in the hippocampus. We now provide evidence of its involvement in the induction of long-term synaptic potentiation in in vitro slices in the cerebral cortex of the rat. 2. Intracellular recordings were made from layer V neurons in the medial frontal cortex, and excitatory synaptic potentials (EPSPs) were evoked by electrical stimulation of layers II/III. Tetanic stimulation of this pathway may induce LTD or LTP or no change at these synapses. First we established experimental conditions under which a long lasting potentiation could be induced with a high incidence (> 60%), namely perfusion of slices with 1 microM bicuculline methiodide, second the use of increased shock duration in the tetanic conditioning stimuli, third and most important the addition of QX-314 to the microelectrode to reduce potassium conductances. Because the potentiation of the mean EPSP slope was significantly greater than the control at 40-min postconditioning, but was declining throughout this period, we refer to it for brevity as LTP, but strictly class it as an LTP-like phenomenon. 3. The nitric oxide (NO) synthase inhibitor interfered with the production of LTP. In the control group of neurons (n = 13) the mean depolarizing slope of the EPSP at 30-min post-conditioning was 142.7 +/- 2% (mean +/- SE) of the prestimulation control.(ABSTRACT TRUNCATED AT 250 WORDS)

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Does endogenous zinc protoporphyrin modulate carbon monoxide formation from heme? Implications for long-term potentiation, memory, and cognitive function

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y93-112 ◽

1993 ◽

Vol 71 (10-11) ◽

pp. 753-754 ◽

Cited By ~ 12

Author(s):

Gerald S. Marks ◽

Kanji Nakatsu ◽

James F. Brien

Keyword(s):

Carbon Monoxide ◽

Heme Oxygenase ◽

Cell Function ◽

Physiological Role ◽

Long Term Potentiation ◽

Biological Properties ◽

Zinc Protoporphyrin ◽

Term Potentiation ◽

Oxygenase Activity

Carbon monoxide, which is formed endogenously from heme catabolism catalyzed by heme oxygenase and shares some of the chemical and biological properties of nitric oxide, may play a similar role as a widespread signal transduction mechanism for the regulation of cell function and communication. Zinc protoporphyrin, an inhibitor of heme oxygenase, prevents induction of long-term potentiation. Zinc protoporphyrin is an endogenous substance and we suggest that it has a physiological role, by modulating heme oxygenase activity and, therefore, formation of carbon monoxide from heme. This in turn would modulate long-term potentiation, memory, and cognitive function.Key words: zinc protoporphyrin, carbon monoxide, heme oxygenase, long-term potentiation.

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2-Deoxyglucose–Induced Long-Term Potentiation in CA1 Is Not Prevented by Intraneuronal Chelator

Journal of Neurophysiology ◽

10.1152/jn.2000.83.1.177 ◽

2000 ◽

Vol 83 (1) ◽

pp. 177-180 ◽

Cited By ~ 6

Author(s):

Yong-Tao Zhao ◽

Krešimir Krnjević

Keyword(s):

Ethylene Glycol ◽

Hippocampal Slices ◽

Long Term Potentiation ◽

Stratum Radiatum ◽

Tetanic Stimulation ◽

Tetraacetic Acid ◽

Ca1 Neurons ◽

Term Potentiation ◽

Stimulation Of

In hippocampal slices, temporary (10–20 min) replacement of glucose with 10 mM 2-deoxyglucose is followed by marked and very sustained potentiation of EPSPs (2-DG LTP). To investigate its mechanism, we examined 2-DG's effect in CA1 neurons recorded with sharp 3 M KCl electrodes containing a strong chelator, 50 or 100 mM ethylene glycol-bis(β-aminoethyl ether)- N, N, N′, N′-tetraacetic acid (EGTA). In most cases, field EPSPs were simultaneously recorded and conventional LTP was also elicited in some cells by tetanic stimulation of stratum radiatum. 2-DG potentiated intracellular EPSP slopes by 48 ± 5.1% (SE) in nine cells recorded with plain KCl electrodes and by 52 ± 6.2% in seven cells recorded with EGTA-containing electrodes. In four of the latter cells, tetanic stimulation (twice 100 Hz for 1 s) failed to evoke LTP (2 ± 1.1%), although field EPSPs were clearly potentiated (by 28 ± 6.9%). Thus unlike tetanic LTP, 2-DG LTP is not readily prevented by postsynaptic intraneuronal injection of EGTA. These findings agree with other evidence that the rise in postsynaptic (somatic) [Ca2+]i caused by 2-DG is not the principal trigger for the subsequent 2-DG LTP and that it may be a purely presynaptic phenomenon.

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The involvement of nonspiking cells in long-term potentiation of synaptic transmission in the hippocampus

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y88-135 ◽

1988 ◽

Vol 66 (6) ◽

pp. 841-844 ◽

Cited By ~ 14

Author(s):

B. R. Sastry ◽

J. W. Goh ◽

P. B. Y. May ◽

S. S. Chirwa

Keyword(s):

Pyramidal Neurons ◽

Hippocampal Slices ◽

Long Term Potentiation ◽

Stratum Radiatum ◽

Ca1 Pyramidal Neurons ◽

Term Potentiation ◽

Ca1 Area ◽

Glial Depolarization ◽

Stimulation Of

In guinea pig hippocampal slices, stimulation of stratum radiatum during depolarization (with intracellular current injections) of nonspiking cells (presumed to be glia) in the apical dendritic area of CA1 pyramidal neurons resulted in a subsequent long-term potentiation of intracellularly recorded excitatory postsynaptic potentials as well as extracellularly recorded population spikes in the CA1 area. Tetanic stimulation of stratum radiatum resulted in a subsequent prolonged depolarization of the presumed glial cells, and this depolarization was smaller when the tetanus was given during the presence of 2-amino-5-phosphonovalerate or when the slices were exposed to Ca2+-free medium containing Mn2+ and Mg2+. These results suggest that glial depolarization is involved as one of the steps in generating long-term potentiation.

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