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

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.

Download Full-text

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.

Download Full-text

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

Learning & Memory ◽

10.1101/lm.5.6.467 ◽

1998 ◽

Vol 5 (6) ◽

pp. 467-480

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 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.

Download Full-text

Oxygen Deprivation Produces Delayed Inhibition of Long-Term Potentiation by Activation of NMDA Receptors and Nitric Oxide Synthase

Journal of Cerebral Blood Flow & Metabolism ◽

10.1097/00004647-199801000-00010 ◽

1998 ◽

Vol 18 (1) ◽

pp. 97-108 ◽

Cited By ~ 17

Author(s):

Yukitoshi Izumi ◽

Hiroshi Katsuki ◽

Ann M. Benz ◽

Charles F. Zorumski

Keyword(s):

Nitric Oxide ◽

Nitric Oxide Synthase ◽

Hippocampal Slices ◽

Long Term Potentiation ◽

Oxygen Deprivation ◽

Delayed Effects ◽

Ca1 Region ◽

Term Potentiation ◽

Oxide Synthase

The acute and delayed effects of anoxia on synaptic transmission and long-term potentiation (LTP) were examined in the CA1 region of rat hippocampal slices. Oxygen deprivation for 20 minutes completely but reversibly depressed excitatory postsynaptic potentials mediated by both N-methyl-d-aspartate receptors (NMDAR) and non-NMDAR. Although LTP was reliably produced by a single tetanus delivered 30 minutes after reoxygenation, LTP could not be induced when a tetanus was delivered 70 to 100 minutes after reoxygenation. A tetanus delivered 100 minutes after reoxygenation produced lasting synaptic enhancement when 100 μmol/L d,l-amino-phosphonovaleric acid (APV), a competitive NMDAR antagonist, was administered during the period of oxygen deprivation. The delayed effects of oxygen deprivation were not blocked when APV was administered after oxygen deprivation. Similarly, the delayed effects on LTP induction were overcome by inhibitors of nitric oxide synthase when the nitric oxide synthase inhibitors were administered during anoxia, but not when administered after oxygen deprivation. These results suggest that untimely activation of NMDAR and nitric oxide release during anoxia produce delayed inhibition of LTP induction and may be involved in the memory defects that occur subsequent to cerebral hypoxia.

Download Full-text

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)

Download Full-text