The role of nitric oxide in hippocampal long-term potentiation

doi:10.1016/0896-6273(92)90288-O

Neuron

Volume 8, Issue 2, February 1992, Pages 211-216

https://doi.org/10.1016/0896-6273(92)90288-O Get rights and content

Abstract

Long-term potentiation is a long-lasting, use-dependent increase in the strength of synaptic connections. We investigated the role of nitric oxide (NO) in determining the duration of potentiation induced by high frequency stimulation of afferents in the CAI region of the rat hippocampus. The calcium/calmodulin-dependent production of NO can be initiated by activation of excitatory amino acid receptors and results in increased levels of cGMP in target cells. Here we report that only a relatively short-term potentiation can be induced in the presence of nitr-l-arginine methyl ester (l-NAME), an NO synthase inhibitor. The effects of l-NAME on the duration of potentiation are partially reversed by coadministration of l-arginine, a precursor of neuronal NO, and by dibutyryl cGMP. Hemoglobin, which binds extracellular NO, also shortens the duration of stimulus-induced potentiation. The results suggest a role for NO in the maintenance of activity-dependent synaptic enhancements, possibly via the generation of cGMP.

References (25)

G.A. Böhme et al.
Possible involvement of nitric oxide in long-term potentiation
Eur. I. Pharmacol.
(1991)
S.J. East et al.
NMDA receptor activation in rat hippocampus induces cyclic GMP formation through the l-arginine nitric oxide pathway
Neurosci. Lett.
(1991)
J. Garthwaite
Glutamate, nitric oxide and cell-cell signalling in the nervous system
Trends Neurosci.
(1991)
J. Larson et al.
Patterned stimulation at the theta frequency is optimal for the induction of hippocampal long-term potentiation
Brain Res.
(1986)
D.M. Lovinger et al.
Protein kinase C inhibitors eliminate hippocampal longterm potentiation
Brain Res.
(1987)
R.C. Malenka
Postsynaptic factors control the duration of synaptic enhancement in area CA1 of the hippocampus
Neuron
(1991)
K.G. Reymann et al.
Polymyxin B, an inhibitor of protein kinase C, prevents the maintenance of synaptic long-term potentiation in hippocampal CA1 neurons
Brain Res.
(1988)
S.H. Snyder et al.
Nitric oxide as a neuronal messenger
Trends Pharmacol. Sci.
(1991)
T.V.P. Bliss et al.
Long-term potentiation of synaptic transmission in the hippocampus: properties and mechanisms
D.S. Bredt et al.
Nitric oxide mediates glutamate-linked enhancement of cGMP levels in the cerebellum

D.S. Bredt et al.

Localization of nitric oxide synthase indicating a neural role for nitric oxide

Nature

(1990)

T.H. Brown et al.

Long-term synaptic potentiation

Science

(1988)

Cited by (460)

The antidepressant-like effect of doxycycline is associated with decreased nitric oxide metabolite levels in the prefrontal cortex
2024, Behavioural Brain Research
Doxycycline is an antibiotic that has shown neuroprotective, anti-inflammatory, and antidepressant-like effects. Low doses of doxycycline revert the behavioral and neuroinflammatory responses induced by lipopolysaccharide treatment in a mice model of depression. However, the molecular mechanisms involved in the antidepressant action of doxycycline are not yet understood. Doxycycline inhibits the synthesis of nitric oxide (NO), which increases after stress exposure. Inducible NO synthase (iNOS) inhibition also causes antidepressant-like effects in animal models sensitive to antidepressant-like effects such as the forced swimming test (FST). However, no direct study has yet investigated if the antidepressant-like effects of doxycycline could involve changes in NO-mediated neurotransmission. Therefore, this study aimed at investigating: i) the behavioral effects induced by doxycycline alone or in association with ineffective doses of a NO donor (sodium nitroprusside, SNP) or an iNOS inhibitor (1400 W) in mice subjected to the FST; and ii) doxycycline effects in NO metabolite levels in the prefrontal cortex and hippocampus these animals. Male mice (8 weeks) received i.p. injection of saline or doxycycline (10, 30, and 50 mg/kg), alone or combined with SNP (0.1, 0.5, and 1 mg/kg) or 1400 W (1, 3, and 10 µg/kg), and 30 min later were submitted to the FST. Animals were sacrificed immediately after, and NO metabolites nitrate/nitrite (NOx) were measured in the prefrontal cortex and hippocampus. Doxycycline (50 mg/kg) reduced both the immobility time in the FST and NOx levels in the prefrontal cortex of mice compared to the saline group. The antidepressant-like effect of doxycycline in the FST was prevented by SNP (1 mg/kg) pretreatment. Additionally, sub-effective doses of doxycycline (30 mg/kg) associated with 1400 W (1 µg/kg) induced an antidepressant-like effect in the FST. Altogether, our data suggest that the reducing NO levels in the prefrontal cortex through inhibition of iNOS could be related to acute doxycycline treatment resulting in rapid antidepressant-like effects in mice.
Current understanding on the role of nitric oxide and therapeutic potential of NO supplementation in schizophrenia
2020, Schizophrenia Research
Pharmacokinetics and pharmacodynamics of nitric oxide mimetic agents
2019, Nitric Oxide - Biology and Chemistry
Drug discovery focusing on NO mimetics has been hamstrung due to its unconventional nature. Central to these challenges is the fact that direct measurement of molecular NO in biological systems is exceedingly difficulty. Hence, drug development of NO mimetics must rely upon measurement of the NO donating specie (i.e., a prodrug) and a downstream marker of efficacy without directly measuring the molecule, NO, that is responsible for biological effect. The focus of this review is to catalog in vivo attempts to monitor the pharmacokinetics (PK) of the NO donating specie and the pharmacodynamic (PD) readout of NO bioactivity.
Pathologic role of nitrergic neurotransmission in mood disorders
2019, Progress in Neurobiology
Citation Excerpt :
PSD95 binds to the cytosolic tail of the NMDA receptor (Christopherson et al., 1999), which directly exposes nNOS to the flux of Ca2+ entering the ion channel of activated NMDA receptors (Kornau et al., 1995; Tomita et al., 2001) leading to NO generation (Fig. 1). NO may also act as a retrograde messenger and diffuse back to the presynaptic terminal (Haley et al., 1992; Shibuki and Okada, 1991) on its target enzyme, soluble guanylyl cyclase (sGC) (Arnold et al., 1977; Boulton et al., 1994). sGC-mediated increase in cyclic guanosine monophosphate (cGMP) levels leads to downstream physiological actions of NO (Hara and Snyder, 2007).
Mood disorders are chronic, recurrent mental diseases that affect millions of individuals worldwide. Although over the past 40 years the biogenic amine models have provided meaningful links with the clinical phenomena of, and the pharmacological treatments currently employed in, mood disorders, there is still a need to examine the contribution of other systems to the neurobiology and treatment of mood disorders. This article reviews the current literature describing the potential role of nitric oxide (NO) signaling in the pathophysiology and thereby the treatment of mood disorders. The hypothesis has arisen from several observations including (i) altered NO levels in patients with mood disorders; (ii) antidepressant effects of NO signaling blockers in both clinical and pre-clinical studies; (iii) interaction between conventional antidepressants/mood stabilizers and NO signaling modulators in several biochemical and behavioral studies; (iv) biochemical and physiological evidence of interaction between monoaminergic (serotonin, noradrenaline, and dopamine) system and NO signaling; (v) interaction between neurotrophic factors and NO signaling in mood regulation and neuroprotection; and finally (vi) a crucial role for NO signaling in the inflammatory processes involved in pathophysiology of mood disorders. These accumulating lines of evidence have provided a new insight into novel approaches for the treatment of mood disorders.
Downregulation of miR-132/212 impairs S-nitrosylation balance and induces tau phosphorylation in Alzheimer's disease
2017, Neurobiology of Aging
Citation Excerpt :
Therefore, miR-132/212 regulates the NOS1 expression and, thereby, NO production and S-nitrosylation in human neural cells. In the brain, physiological levels of NO mediate normal neuronal processes such as long-term potentiation, contributing to memory and learning formation (Haley et al., 1992; Izumi et al., 1992), and even under moderate nitrosative stress, NO can still facilitate neuroprotection (Nakamura et al., 2013). However, high and prolonged production of NO can contribute to synaptic damage and neuronal apoptosis via aberrant SNO of numerous critical proteins.
MicroRNA-132 is markedly downregulated in Alzheimer's disease (AD) and related tauopathies, and its levels are closely associated with tau pathology in AD. Whether and how miR-132 contributes to pathology in these neurodegenerative diseases remains unclear. Here, we show that miR-132 and its paralogue miR-212 directly regulate the expression of neuronal nitric oxide synthase (NOS1) through the primate-specific binding site. Inhibition of miR-132 in primary human neurons and neural cells leads to increased NOS1 levels and triggers excessive production of nitric oxide, followed by aberrant S-nitrosylation (SNO) of specific proteins associated with neurodegeneration and tau pathology, such as cyclin-dependent kinase 5, dynamin-related protein 1, and glyceraldehyde-3-phosphate dehydrogenase. This, in turn, increases tau phosphorylation at disease associated Ser396, Ser404, and Ser202 sites, and impairs neural viability. Our findings indicate that downregulation of miR-132/212 disturbs the balance of S-nitrosylation and induces tau phosphorylation in a NOS1-dependent way, and thereby may contribute to the pathogenesis of AD and other tauopathies.
1400 W ameliorates acute hypobaric hypoxia/reoxygenation-induced cognitive deficits by suppressing the induction of inducible nitric oxide synthase in rat cerebral cortex microglia
2017, Behavioural Brain Research
Citation Excerpt :
NO is a bioactive molecule and is an important messenger molecule in the brain [15]. NO plays a role in cognition, which may be related to synaptic plasticity of the hippocampus [16,17]. NO is synthesized from L-arginine by the enzyme nitric oxide synthase (NOS) [18].
Nitric oxide (NO) is involved in neuronal modifications, and overproduction of NO contributes to memory deficits after acute hypobaric hypoxia-reoxygenation. This study investigated the ability of the iNOS inhibitor 1400 W to counteract spatial memory deficits following acute hypobaric hypoxia-reoxygenation, and to affect expression of NOS, NO, 3-NT and MDA production, and apoptosis in rat cerebral cortex. We also used primary rat microglia to investigate the effect of 1400 W on expression of NOS, NO, 3-NT and MDA production, and apoptosis. Acute hypobaric hypoxia-reoxygenation impaired spatial memory, and was accompanied by activated microglia, increased iNOS expression, NO, 3-NT and MDA production, and neuronal cell apoptosis in rat cerebral cortex one day post-reoxygenation. 1400 W treatment inhibited iNOS expression without affecting nNOS or eNOS. 1400 W also reduced NO, 3-NT and MDA production, and prevented neuronal cell apoptosis in cerebral cortex, in addition to reversing spatial memory impairment after acute hypobaric hypoxia-reoxygenation. Hypoxia-reoxygenation activated primary microglia, and increased iNOS and nNOS expression, NO, 3-NT, and MDA production, and apoptosis. Treatment with 1400 W inhibited iNOS expression without affecting nNOS, reduced NO, 3-NT and MDA production, and prevented apoptosis in primary microglia. Based on the above findings, we concluded that the highly selective iNOS inhibitor 1400 W inhibited iNOS induction in microglial cells, and reduced generation of NO, thereby mitigating oxidative stress and neuronal cell apoptosis in the rat cerebral cortex, and improving the spatial memory dysfunction caused by acute hypobaric hypoxia-reoxygenation.

View all citing articles on Scopus

View full text

Neuron

ArticleThe role of nitric oxide in hippocampal long-term potentiation

Abstract

Eur. I. Pharmacol.

Neurosci. Lett.

Trends Neurosci.

Brain Res.

Brain Res.

Neuron

Brain Res.

Trends Pharmacol. Sci.

Long-term potentiation of synaptic transmission in the hippocampus: properties and mechanisms

Nitric oxide mediates glutamate-linked enhancement of cGMP levels in the cerebellum

Localization of nitric oxide synthase indicating a neural role for nitric oxide

Nature

Long-term synaptic potentiation

Science

Article
The role of nitric oxide in hippocampal long-term potentiation