Altered synaptic plasticity and memory formation in nitric oxide synthase inhibitor-treated rats.

Böhme, Georg Andrees; Bon, Christelle L. M.; Lemaire, Martine; Reibaud, M.; Piot, O.; Stutzmann, Jean‐Marie; Doble, Adam; Blanchard, Jean‐Charles

doi:10.1073/pnas.90.19.9191

Cited by 300 publications

(155 citation statements)

References 37 publications

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“…regulation of central nervous system blood flow, neurotransmitter release from cholinergic nerve fibres and the functional regulation of organs with nitrergic innervation [32].…”

Section: Physiological Functions Of Nnosmentioning

confidence: 99%

Neuronal Nitric Oxide Synthase

Arami¹,

Jameie²,

AkbarMoosavi³

2017

Nitric Oxide Synthase - Simple Enzyme-Complex Roles

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Nitric oxide synthase (NOS), a flavo-hemoprotein, regulates nitric oxide (NO) synthesis that has dual biological activities: as an important signalling molecule in vasodilatation and neurotransmission at low concentrations and at higher concentrations as a defensive cytotoxin. In central and peripheral nervous system, neuronal NOS (nNOS) produces NO that has been implicated in modulating physiological functions such as synaptic plasticity, learning, memory and neurogenesis as well as some pathological conditions in which overproduction of NO may lead to the generation of highly reactive species, such as peroxynitrite and stable nitrosothiols, which may cause irreversible cell damage in excitotoxicity, ischaemia, Parkinson, Alzheimer's disease (AD) and depression. NOSderived NO also involves in regulation of blood pressure, smooth muscle relaxation and gut peristalsis via peripheral nitrergic nerves.

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“…regulation of central nervous system blood flow, neurotransmitter release from cholinergic nerve fibres and the functional regulation of organs with nitrergic innervation [32].…”

Section: Physiological Functions Of Nnosmentioning

confidence: 99%

Neuronal Nitric Oxide Synthase

Arami¹,

Jameie²,

AkbarMoosavi³

2017

Nitric Oxide Synthase - Simple Enzyme-Complex Roles

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“…Consistent with these cellular studies, inhibition of NOS activity may disrupt learning (refs. [16][17][18][19], but see refs. 20 and 21).…”

mentioning

confidence: 99%

Molecular and biochemical characterization of dNOS: a Drosophila Ca2+/calmodulin-dependent nitric oxide synthase.

Regulski

Tully²

1995

Proc. Natl. Acad. Sci. U.S.A.

227

144

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Nitric oxide (NO) is an intercellular messenger involved with various aspects of mammalian physiology ranging from vasodilation and macrophage cytotoxicity to neuronal transmission. NO is synthesized from L-arginine by NO synthase (NOS). Here, we report the cloning of a Drosophila NOS gene, dNOS, located at cytological position 32B.The dNOS cDNA encodes a protein of 152 kDa, with 43% amino acid sequence identity to rat neuronal NOS. Like mammalian NOSs, DNOS protein contains putative binding sites for calmodulin, FMN, FAD, and NADPH. DNOS activity is Ca2+/calmodulin dependent when expressed in cell culture. An alternative RNA splicing pattern also exists for dNOS, which is identical to that for vertebrate neuronal NOS. These structural and functional observations demonstrate remarkable conservation of NOS between vertebrates and invertebrates.Nitric oxide (NO) is synthesized by NO synthases (NOSs) during conversion of L-arginine to L-citrulline (for reviews, see refs. 1 and 2). Biochemical characterization of NOSs has distinguished two general classes: (i) constitutive, dependent on exogenous Ca2+/calmodulin, and (ii) inducible, independent of exogenous Ca2+/calmodulin. Analyses of cDNA clones have identified three distinct NOS genes in mammals (3-6): neuronal, endothelial, and macrophage. The neuronal and endothelial NOSs are constitutive, and the macrophage NOS is inducible. The nomenclature for these different isoforms used here is historical, as it is clear now that one or more isoforms can be present in the same tissue (7).As a diffusible, free-radical gas, NO is a multifunctional messenger affecting many diverse aspects of mammalian physiology (for review, see ref. 8), such as regulation of vascular tone, macrophage-mediated cytotoxicity, and cell-cell interactions in the nervous system, including synaptogenesis and apoptosis during development of the rat central nervous system (9) and during neuronal cell differentiation (10). NO also appears to be involved with long-term potentiation in hippocampus and with long-term depression in cerebellum, two forms of synaptic plasticity that may underlie behavioral plasticity (11-15). Consistent with these cellular studies, inhibition of NOS activity may disrupt learning (refs. 16-19, but see refs. 20 and 21).Many of the above results are based on pharmacological studies using inhibitors of NOS or donors of NO. Interpretations of such studies usually are limited because the drugs interact with more than one target and cannot be delivered to specific sites. A molecular genetic approach can overcome these problems, however, by disrupting a specific gene, the product of which may be one of the drug's targets. Recently, such an approach has been attempted in mice via generation of a knockout mutation of the neuronal NOS (nNOS) (22).While nNOS mutants appeared fully viable and fertile, minor defects in stomach morphology and hippocampal long-term potentiation were detected (22, 23). Taken together, the above reports suggest roles for NO in developmental and behav...

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“…In line with this conclusion, previous studies have also demonstrated that odor perception is not altered by NO blockade. Specifically, NO did not impair maternal recognition in the lambs (Kendrick et al 1997), nor did it affect the time adult rats spent investigating the novel juvenile (Bohme et al 1993). As our habituation task serves as a measure of olfactory short-term memory, these results also suggest that this specific type of memory remains intact in NO deficient animals.…”

Section: Odor Discrimination and Olfactory Memory Generalizationmentioning

confidence: 99%

Neuronal nitric-oxide synthase deficiency impairs the long-term memory of olfactory fear learning and increases odor generalization

2013

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Experience-induced changes associated with odor learning are mediated by a number of signaling molecules, including nitric oxide (NO), which is predominantly synthesized by neuronal nitric oxide synthase (nNOS) in the brain. In the current study, we investigated the role of nNOS in the acquisition and retention of conditioned olfactory fear. Mice lacking nNOS received six training trials, each consisting of an odor-CS co-terminating with a foot shock-US. Mice showed reduced freezing responses to the trained odor 24 h and 7 d after training, compared to wild-type mice. Pretraining systemic injections of the NO donor, molsidomine, rescued fear retention in nNOS knockout mice. In wildtype mice, pretraining systemic injections of L-NAME, a nonspecific nNOS blocker, disrupted odor-CS fear retention in a dose-dependent manner. To evaluate whether NO signaling is involved in generalization of fear memories, nNOS knockout mice and wild-type mice receiving L-NAME were trained to one odor and tested with a series of similar odors. In both cases, we found increased generalization, as measured by increased freezing to similar, unpaired odors. Despite the impairment in fear memory retention and generalization, neither mice receiving injections of L-NAME nor nNOS knockout mice showed any deficits in either novel odor investigation time or odor habituation, suggesting intact olfactory perception and short-term memory olfactory learning. These results support a necessary role for neuronal NO signaling in the normal expression and generalization of olfactory conditioned fear.The ability to learn and retain memories is dependent on several transmitters. Currently, there is much interest in the involvement of nitric oxide (NO) signaling in long-term memory formation (Bredt and Snyder 1992;Hawkins et al. 1994;Garthwaite 2008;Kelley et al. 2011). NO is generated from the amino acid L-arginine by the enzyme NO synthase (NOS) and functions as a retrograde neurotransmitter. Due to the diffusible nature of NO and its relationship with NMDA receptor activation, neurons containing the neuronal isoform of NOS (nNOS) could be involved in driving synaptic strength changes during learning processes such as longterm memory Zhuo et al. 1994;Garthwaite 2008).Fear conditioning is a useful tool in studying the neuronal mechanisms involved in the formation of long-term memory and fear-related systems. Rodents can quickly and reliably learn a fear association between a conditioned stimulus (CS) and an aversive stimulus (US), such as a foot shock (Young and Fanselow 1992). The role nNOS plays in fear learning has been investigated using contextual fear conditioning, as well as visual and auditory cues as the CS (Schafe et al. 2005;Kelley et al. 2010Kelley et al. , 2011Overeem et al. 2010). And although the nNOS inhibitor 7-nitroindazole showed no disruption in the acquisition and expression of the contextual fear conditioning (Maren 1998), it was demonstrated that animals lacking the nNOS gene (Nos1or nNOS knockout) have shown deficits in fear condit...

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Altered synaptic plasticity and memory formation in nitric oxide synthase inhibitor-treated rats.

Cited by 300 publications

References 37 publications

Neuronal Nitric Oxide Synthase

Neuronal Nitric Oxide Synthase

Molecular and biochemical characterization of dNOS: a Drosophila Ca2+/calmodulin-dependent nitric oxide synthase.

Neuronal nitric-oxide synthase deficiency impairs the long-term memory of olfactory fear learning and increases odor generalization

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