Concentration dynamics of nitric oxide in rat hippocampal subregions evoked by stimulation of the NMDA glutamate receptor

Ledo, Ana; Barbosa, Rui M.; Gerhardt, Greg A.; Cadenas, Enrique; Laranjinha, João

doi:10.1073/pnas.0503624102

Cited by 90 publications

(73 citation statements)

References 69 publications

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“…It is noteworthy that interictal activity was still present in NO-deprived slice cultures, suggesting that NO influences the entrainment of dynamically coupled oscillators rather than the pacemaker activity itself. This is in line with the concept that freely diffusible NO is a good candidate for increasing synchrony of adjacent ensembles of pyramidal neurons (Dzhala and Staley, 2003;Ledo et al, 2005;Derchansky et al, 2006). SLE initiation might involve selective activation of certain interneuron populations, as suggested in human temporal lobe epilepsy (Wendling et al, 2005).…”

Section: Effects Of Endogenous No On Sle Initiationsupporting

confidence: 59%

Endogenous Nitric Oxide Is a Key Promoting Factor for Initiation of Seizure-Like Events in Hippocampal and Entorhinal Cortex Slices

Kovacs¹,

Rabanus²,

Otáhal³

et al. 2009

Journal of Neuroscience

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Nitric oxide (NO) modulates synaptic transmission, and its level is elevated during epileptic activity in animal models of epilepsy. However, the role of NO for development and maintenance of epileptic activity is controversial. We studied this aspect in rat organotypic hippocampal slice cultures and acute hippocampal-entorhinal cortex slices from wild-type and neuronal NO synthase (nNOS) knock-out mice combining electrophysiological and fluorescence imaging techniques. Slice cultures contained nNOS-positive neurons and an elaborated network of nNOS-positive fibers. Lowering of extracellular Mg 2ϩ concentration led to development of epileptiform activity and increased NO formation as revealed by NO-selective probes, 4-amino-5-methylamino-2Ј,7Ј-difluorofluorescein and 1,2-diaminoanthraquinone sulfate. NO deprivation by NOS inhibitors and NO scavengers caused depression of both EPSCs and IPSCs and prevented initiation of seizure-like events (SLEs) in 75% of slice cultures and 100% of hippocampal-entorhinal cortex slices. This effect was independent of the guanylyl cyclase/cGMP pathway. Suppression of SLE initiation in acute slices from mice was achieved by both the broad-spectrum NOS inhibitor N-methyl-L-arginine acetate and the nNOS-selective inhibitor 7-nitroindazole, whereas inhibition of inducible NOS by aminoguanidine was ineffective, suggesting that nNOS activity was crucial for SLE initiation. Additional evidence was obtained from knock-out animals because SLEs developed in a significantly lower percentage of slices from nNOS Ϫ/Ϫ mice and showed different characteristics, such as prolongation of onset latency and higher variability of SLE intervals. We conclude that enhancement of synaptic transmission by NO under epileptic conditions represents a positive feedback mechanism for the initiation of seizure-like events.

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Section: Effects Of Endogenous No On Sle Initiationsupporting

confidence: 59%

Endogenous Nitric Oxide Is a Key Promoting Factor for Initiation of Seizure-Like Events in Hippocampal and Entorhinal Cortex Slices

Kovacs¹,

Rabanus²,

Otáhal³

et al. 2009

Journal of Neuroscience

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“…The glutamate-dependent NO production in hippocampus is of particular relevance because of NO involvement in the regulation of plasticity, such as learning and memory, and cell death associated with neurodegeneration (Laranjinha and Ledo, 2007;Pacher et al, 2007). We have previously measured the diffusional spread of NO in hippocampal slices elicited by stimulation of the glutamate NMDA receptor which, for a physiological oxygen tension, was found to be a few hundred (400) microns (Ledo et al, 2005). However, considering that (i) in the hippocampal slice, blood circulation is inoperative and in vivo a functional vascularization may effectively remove NO and (ii) the mean distance between capillaries in the brain is smaller than 400 lm, we expected the diffusion of NO to be smaller in vivo as compared with the one determined in the perfused slices.…”

Section: Measurement Ofmentioning

confidence: 98%

In vivo modulation of nitric oxide concentration dynamics upon glutamatergic neuronal activation in the hippocampus

et al. 2011

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Nitric oxide ((•)NO) is a labile endogenous free radical produced upon glutamatergic neuronal activity in hippocampus by neuronal nitric oxide synthase (nNOS), where it acts as a modulator of both synaptic plasticity and cell death associated with neurodegeneration. The low CNS levels and fast time dynamics of this molecule require the use of rapid analytical methods that can more accurately describe its signaling in vivo. This is critical for understanding how the kinetics of (•)NO-dependent signaling pathways is translated into physiological or pathological functions. In these studies, we used (•)NO selective microelectrodes coupled with rapid electrochemical recording techniques to characterize for the first time the concentration dynamics of (•)NO endogenously produced in hippocampus in vivo following activation of ionotropic glutamate receptors. Both L-glutamate (1-100 mM) and N-methyl-D-aspartate (NMDA; 0.01-5 mM) produced transient, dose-dependent increases in extracellular (•)NO concentration. The production of (•)NO in the hippocampus by glutamate was decreased by the nNOS inhibitor 7-NI. Intraperitoneal administration of the NMDA receptor blocker, MK-801, and the inhibitor of α-amino-3-hydroxy-5-methyl-4-isoazolepropionic acid (AMPA) receptor, NBQX, applied locally greatly attenuated glutamate-evoked overflow of (•)NO. Thus, (•)NO overflow elicited by activation of glutamate receptors appeared to result from an integrated activation of ionotropic glutamate receptors, both of the NMDA and AMPA receptors subtypes. Additionally, distinct concentration dynamics was observed in the trisynaptic loop with stronger and longer lasting effects of glutamate activation on (•)NO overflow seen in the CA1 region as compared with the dentate gyrus. Overall, the results provide a quantitative and temporal basis for a better understanding of (•)NO activity in the rat hippocampus.

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“…Nitric oxide ( NO) is an endogenously produced gaseous free radical implicated in a number of cellular events in the central nervous system (CNS) (Dawson and Dawson, 1998;Gegg et al, 2005;Ledo et al, 2005;Pacher et al, 2007). In the hippocampus, NO has been implicated in a pathway supporting plasticity by means of glutamatergic receptors activation (Morris et al, 1982;O'Dell et al, 1991;Schuman and Madison, 1991;Bliss and Collingridge, 1993).…”

Section: Introductionmentioning

confidence: 99%

Stimulation of NMDA and AMPA glutamate receptors elicits distinct concentration dynamics of nitric oxide in rat hippocampal slices

2008

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Nitric oxide ((*)NO) is an intercellular messenger implicated in memory formation and neurodegeneration in the hippocampus. Owing to its physical and chemical properties, the concentration dynamics of (*)NO is a critical issue in determining its bioactivity as a signaling molecule. Its production is closely related to glutamate N-methyl-D-aspartate (NMDA) receptors, following a rise in intracellular calcium levels. However, that dependent on alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptors remains elusive and controversial, despite reports describing a role for these receptors in other brain regions, largely because of lack of quantitative and dynamic measurements of (*)NO. Using a (*)NO-selective microsensor inserted in the diffusional spread of (*)NO in the CA1 region of rat hippocampal slices, we measured its real-time endogenous production, following activation of ionotropic glutamate receptors and under tissue physiological oxygen tension. Both NMDA and AMPA stimulation resulted in a concentration-dependent (*)NO production but encompassing distinct kinetics for lag phases and slower rates of (*)NO production were observed for AMPA stimulation. Robustness of the results was achieved instrumentally and pharmacologically, by means of nitric oxide synthase (NOS) inhibitors and antagonists of NMDA (D-(-)-2-amino-5-phosphonopentanoic acid, AP5) and AMPA (2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide, NBQX) receptors. When using glutamate as a stimulus, (*)NO production was of lower magnitude in the presence of AP5 plus NBQX than with AP5 alone, suggesting that even when NMDA receptors are inhibited Ca(2+) rises to levels to induce a peak of (*)NO from the background. Whereas extracellular Ca(2+) was required for the (*)NO signals, Philanthotoxin-4,3,3 (PhTX-4,3,3) a toxin used to target Ca(2+)-permeable AMPA receptors, attenuated (*)NO production. These observations are interpreted on basis of a distinct coupling between the glutamate receptors and neuronal NOS. A role for Ca(2+)-permeable AMPA receptors in the Ca(2+) activation of neuronal NOS is suggested.

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Concentration dynamics of nitric oxide in rat hippocampal subregions evoked by stimulation of the NMDA glutamate receptor

Abstract: carbon fiber microelectrode ͉ NO diffusional spread ͉ hippocampus

Cited by 90 publications

References 69 publications

Endogenous Nitric Oxide Is a Key Promoting Factor for Initiation of Seizure-Like Events in Hippocampal and Entorhinal Cortex Slices

Endogenous Nitric Oxide Is a Key Promoting Factor for Initiation of Seizure-Like Events in Hippocampal and Entorhinal Cortex Slices

In vivo modulation of nitric oxide concentration dynamics upon glutamatergic neuronal activation in the hippocampus

Stimulation of NMDA and AMPA glutamate receptors elicits distinct concentration dynamics of nitric oxide in rat hippocampal slices

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