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1 Department of Physiology and Pharmacology and Instituto Nazionale Fisica della Materia, Pavia University, 27100, Pavia; 2 Department of Evolutionary and Functional Biology, Parma University, 34100, Parma, Italy; 3 Department of Neurophysiology, Brain Research Institute, Niigata University, 951-8585, Niigata, Japan
Submitted 22 April 2003; accepted in final form 14 May 2003
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONDISCLOSUREREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONDISCLOSUREREFERENCES |
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; Hawkins et al. 1998; Snyder 1992). The NO pathway is initiated by N-methyl-D-aspartate (NMDA) receptor activation, causing Ca2+ influx. Ca2+ then activates nitric oxide synthase (NOS), which deaminates arginine to citrulline, releasing NO. NO is then supposed to diffuse transsynaptically. Retrograde diffusion from post- to presynaptic terminals may enhance neurotransmitter release through a cGMP-dependent mechanism, as demonstrated in neuron pairs in culture (Arancio et al. 1996) and proposed for certain hippocampal synapses (Bon and Garthwaite 2001, 2003; Malen and Chapman 1997; Schuman et al. 1994). Anterograde diffusion may regulate postsynaptic responsiveness, as proposed in cerebellar parallel fiber–Purkinje cell long-term potentiation and depression (LTP and LTD; Casado et al. 2002; Lev-Ram et al. 2002; Shibuki and Kimura 1997; Shibuki and Okada 1991; but see Linden and Connor 1992).
Direct demonstration of presynaptic changes is critical to validate the involvement of NO in retrograde signaling. Presynaptic current changes during LTP have recently been revealed at the cerebellar mossy fiber–granule cell synapse (Maffei et al. 2001). Granule cells are endowed with NMDA receptors and NOS (Baader and Shilling 1996; Bredt et al. 1990; Garthwaite et al. 1988; Schilling et al. 1994). Pharmacological NMDA receptor stimulation or exogenous NO application causes cGMP elevation in the cerebellar granule cell layer (Bellamy et al. 2002; Griffiths and Garthwaite 2001; Southam and Garthwaite 1991a,b; Southam et al. 1991). Nonetheless, the potential involvement of NO signaling in LTP at the cerebellar mossy fiber–granule cell relay (Armano et al. 2000; D'Angelo et al. 1999; Hansel et al. 2001) remained unknown.
In this paper we show that high-frequency mossy fiber stimulation caused a significant NMDA receptor- and NOS-dependent release of NO in the granular cell layer of rat cerebellar slices. Inhibiting NOS, scavenging extracellular NO, or blocking the NO target guanylyl cyclase prevented LTP. Moreover, LTP could be induced by the NO donor 2-(N,N-diethylamino)-diazenolate-2-oxide·Na (DEA-NO). LTP was accompanied by consensual changes in the mossy fiber terminal current. These observations thus reveal a critical role for NO in mossy fiber–granule cell LTP and in the regulation of presynaptic terminal excitability.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONDISCLOSUREREFERENCES |
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; see Fig. 1). Control stimulation was performed at 0.1 Hz and volley stability was assessed through P1 (experiments with more than 10% P1 changes were discarded). The presynaptic terminal current was measured at N1 peak (or at N1b peak when it could be distinguished). The postsynaptic response was measured at N2 peak and as SN amplitude 50 ms following mossy fiber stimulation, the nature of which is explained in Eccles et al. (1967) and reconsidered in Maffei et al. (2001). 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-dione (ODQ), NG-nitro-L-arginine (L-NNA), 2-amino-5-phosphonovaleric acid (APV), and 7-chlorokynurenic acid were purchased from Tocris Cookson (UK); DEA-NO was purchased from Alexis (San Diego, CA), and myoglobin and all other chemicals were purchased from Sigma-Aldrich. Drugs were bath-perfused after proper dilution in Krebs solution.
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Oxy-myoglobin (MbO2) was prepared as reported by Lev-Ram et al. (2002) by dissolving 5 mM myoglobin in Krebs solution, adding 20 mM Na-dithionite to reduce meta-myoglobin to deoxy-myoglobin, separating the excess dithionite by Sephadex G25, and re-oxidizing myoglobin to MbO2. The concentration of purified MbO2 was evaluated from its absorption at 416 and 453 nm. The MbO2 solution was stored at 4°C and used within 3 days.
DEA-NO was prepared as reported by Bon and Garthwaite (2001). Briefly, 10 mM DEA-NO was dissolved in 10 mM NaOH and stored frozen for <24 h before use. DEA-NO was then dissolved in Krebs solution to its final concentration (10 µM) immediately before use. Since NO released during DEA-NO application peaks in 2–3 min and then decays to 0 in about 20 min (Griffiths and Garthwaite 2001), reconstituted DEA-NO solutions were immediately perfused into the recording chamber. DEA-NO perfusion was maintained for 2 min before switching back to Krebs solution.
NO measurements were performed with electrochemical probes as reported in Shibuki and Okada (1991) and Shibuki and Kimura (1997). Probe linearity was tested by NO solutions of 4, 8, and 12 nM prepared with the NO donor (±)-(E)-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexeneamine (NOR3). The probe tip had a 50-µm diameter and was positioned into the granular cell layer at 300–500 µm from the molecular layer. With this experimental arrangement the probe should not be able to detect significant NO signals generated by parallel fibers since these are severed in para-sagittal slices and extend their action within just 150 µm (Jacoby et al. 2001). Moreover, theoretical models predict that, since granule cells cause a strong NO inactivation (Griffith and Garthwaite 2001), the NO signal at 300–500 µm should fall below the nanomolar range (Wood and Garthwaite 1994).
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONDISCLOSUREREFERENCES |
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), the focal current comprised a presynaptic response (P1/N1) corresponding to the spike volley and the mossy fiber terminal current and a postsynaptic response (N2/SN) generated by excitatory postsynaptic potentials (EPSP) and spikes in granule cells (Fig. 1). The mossy fiber terminal current either could be included into N1 or emerge as a component (N1b) distinct from the volley (P1/N1a) (e.g., Fig. 3).
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At this synapse, LTP depends on postsynaptic membrane depolarization and subsequent Ca2+ permeation through NMDA channels during high-frequency mossy fiber stimulation (D'Angelo et al. 1999). LTP could be induced by eight 100-ms bursts at 100 Hz applied every 250 ms (
-burst stimulation, TBS), but not by a single 100-ms 100-Hz burst, and consisted of a simultaneous N1 and N2/SN increase (n = 5; Fig. 1; see also Maffei et al. 2001). Marginal improvement (<15% increase in either N1 or N2/SN; n = 3, not shown) was obtained by applying a second TBS, confirming that TBS nearly saturates LTP as observed using pairing protocols in whole cell recording (Rossi et al. 2002). A similar LTP was also obtained with a single 1-s 100-Hz burst (long-burst stimulation, LBS; n = 5; Fig. 1), as previously observed using granule cell perforated-patch recordings (Armano et al. 2000).
It was discovered earlier that NMDA causes NO release from granule cell homogenates (Garthwaite et al. 1988) and the observation has been confirmed thereafter (Griffith and Garthwaite 2001). Here we investigated whether NO could be released during LTP induction by high-frequency mossy fiber activity. To this aim we positioned an NO electrochemical probe in the granular cell layer of cerebellar slices (Shibuki and Kimura 1997; Shibuki and Okada 1991) and stimulated mossy fibers for 1 s at 100 Hz (LBS, cf. Fig. 1). LBS caused an NO transient (6.2 ± 2.8 nM; n = 5) peaking in 1.5 ± 0.5 s and decaying with a time constant of 3.6 ± 1.2 s (Fig. 2). The NO transient was comparable to that measured in the molecular layer on parallel fiber stimulation (Shibuki and Kimura 1997; Shibuki and Okada 1991). The NO transient was blocked by perfusing the NOS inhibitor 100 µM L-NNA (3.1 ± 5.4%; n = 3; Fig. 2A) and was strongly reduced by perfusing the NMDA receptor antagonists, 100 µM APV and 50 µM 7-Cl-kyn (26.5 ± 22.8%; n = 3; Fig. 2B).
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To understand whether NO released following mossy fiber stimulation was involved in LTP, we pharmacologically blocked two critical steps of the NO cascade (Fig. 3). Indeed, the potentiating effect of TBS on N1 and N2/SN was prevented by applying either the NOS inhibitor, 100 µM L-NNA (n = 5; Southam et al. 1991), or the soluble guanylyl cyclase (sGC) inhibitor, 10 µM ODQ (n = 5), which were shown to prevent cGMP production and LTP in hippocampal slices (Boulton et al. 1995).
To verify whether NO has to diffuse through the extracellular space before reaching sensitive targets, we perfused the NO scavenger 10 µM MbO2 (Arancio et al. 1996; Lev-Ram et al. 2002; Southam and Garthwaite 1991a). MbO2 prevented TBS potentiation in both N1 and N2/SN (n = 5). It should be noted that L-NNA, ODQ, or MbO2 perfusion did not affect N1 and N2/SN during basal neurotransmission.
If NO is involved in LTP, then it should cause potentiation when applied exogenously. Different NO donors were reported to increase cGMP production in the granular layer of cerebellar slices (Southam and Garthwaite 1991b). We have used DEA-NO, which caused LTP in hippocampal preparations (Bon and Garthwaite 2003). To achieve a relatively fast and transient NO stimulation, we perfused 10 µM DEA-NO for 2 min. A similar protocol is expected to activate sGC despite NO inactivation by cerebellar granule cells (cf. Fig. 1A in Griffith and Garthwaite 2002). Indeed, 2-min 10 µM DEA-NO application during basal low-frequency stimulation induced LTP in all the five preparations tested (Fig. 4A). Potentiation occurred simultaneously in N1, N2, and SN.
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After inducing LTP by DEA-NO application, TBS could not induce further potentiation (n = 4; Fig. 4A). Likewise, following LTP induction by TBS, 2-min 10 µM DEA-NO application could not induce further potentiation (n = 4; Fig. 4B). Mutual occlusion of LTP induced by NO and TBS indicates that they share a mechanism in common.
If NO determines LTP through a cGMP-mediated pathway, its action should be prevented by blocking sGC. Indeed, application of 10 µM ODQ prevented 2-min 10 µM DEA-NO application from inducing LTP (n = 4; Fig. 5A).
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It was suggested that exogenous NO reinforces endogenous mechanisms involving NMDA receptors (Bon and Garthwaite 2001). We therefore applied 50 µM APV +25 µM 7-Cl-kyn that considerably reduced SN (Fig. 5B; cf. Maffei et al. 2001). Then, 2-min 10 µM DEA-NO application still caused LTP (n = 4). Exogenous NO may require ongoing afferent stimulation to enhance LTP (Bon and Garthwaite 2001; but see Jacoby et al. 2001; Lev-Ram et al. 2002). In four experiments, interrupting test stimulation during 2-min 10 µM DEA-NO perfusion did not prevent LTP (Fig. 5C).
Figure 6 compares LTP obtained with DEA-NO and high-frequency stimulation. There was no significant difference in N1 or N2 potentiation (P > 0.31 and P > 0.8; unpaired t-test) caused by DEA-NO (either with or without stimulation or with NMDA receptor blockade; n = 12) compared with that caused by high-frequency stimulation (TBS and LBS; n = 11). However, SN was smaller (P < 0.04, unpaired t-test) in LTP caused by DEA-NO (either with or without stimulation; n = 8) than in LTP caused by high-frequency stimulation (TBS and LBS; n = 11), probably reflecting NO-dependent inhibition of NMDA receptors (Manzoni et al. 1992). Finally, we noticed that changes in either N1, N2, or SN were not significantly different across the various conditions of DEA-NO application (always P > 0.33; unpaired t-test).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONDISCLOSUREREFERENCES |
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The demonstration that NO is required for cerebellar mossy fiber–granule cell LTP is based on three main lines of evidence. First, NO was produced by mossy fiber stimulation in a NOS and NMDA receptor-dependent manner. During high-frequency stimulation capable of inducing LTP, NO reached a concentration around 6 nM. Since the dose-response curve of sGC shows an EC50 = 2 nM and saturates at 6 nM in cerebellar cell suspension, NO should fully activate sGC during LTP induction (Bellamy et al. 2002; Griffith and Garthwaite 2001). Second, LTP was blocked by inhibiting several steps of the NO cascade, including NO production by NOS, NO diffusion in the extracellular space, and sGC activation. Third, LTP was induced by the NO donor, DEA-NO. DEA-NO- and TBS-dependent LTP showed similar inhibition by sGC block and were mutually occlusive. This indicates that 10 µM DEA-NO releases enough NO to saturate LTP induction through guanylyl cyclase activation, consistent with nearly maximal elevation of cGMP levels in the granular cell layer (Bellamy et al. 2002; Bon and Garthwaite 2001). We also noted that DEA-NO-dependent LTP persisted during NMDA receptor blockade or interruption of mossy fiber stimulation, suggesting that exogenous NO is sufficient for LTP induction (Jacoby et al. 2001; Lev-Ram et al. 2002; Malen and Chapman 1997; but see Bon and Garthwaite 2001, 2003). Finally, during DEA-NO application we did not observe synaptic depression, a process that depends on cGMP-independent reduction of mitochondrial respiration (Bon and Garthwaite 2001), maybe reflecting short duration of NO stimulation.
Owing to their intense NOS and NMDA receptor expression (Baader and Schilling 1996; Bredt et al. 1990; Schilling et al. 1994), granule cells are the most likely sites of NO production in the granular cell layer. Indeed, NO is released by cerebellar homogenates stimulated with NMDA (Garthwaite et al. 1988) and increases in the extracellular space during mossy fiber stimulation (see Fig. 3). Accordingly, mossy fiber stimulation raises extracellular arginine, the NO precursor, supporting activation of the NO pathway (Hansel et al. 1992). The preventative action of MbO2 on presynaptic current changes during LTP suggests that NO acts transcellularly. In fact, although extracellular MbO2 may also reduce intracellular NO (Lancaster 1994), MbO2 prevents NMDA receptor-dependent cGMP increase in mossy fiber terminals and glial cells rather than in granule cells (Southam and Garthwaite 1991a; Southam et al. 1991). Present and previous data thus support a model in which postsynaptic NMDA receptor stimulation leads to NOS activation, NO production, and NO diffusion to presynaptic terminals where sGC is activated, producing cGMP (Arancio et al. 2001). It should be noted that blocking NMDA receptor-dependent Ca2+ influx (D'Angelo et al. 1999; Maffei et al. 2001) and inhibiting NOS and sGC (see Fig. 2) turned the system toward long-term depression, suggesting that NO is critical for determining the sign of synaptic plasticity.
A cGMP-dependent channels regulation (Arancio et al. 1996) may determine the presynaptic current changes observed during LTP. cGMP can enhance Ca2+ currents (Hirooka et al. 2000), reduce K+ currents (Cetiner and Bennet 1993), and activate nucleotide-gated cationic channels (Savchenko et al. 1997; Zhuo et al. 1994), whose presence has recently been reported in the cerebellar granule cell layer (Kingston et al. 1999; Strijbos et al. 1999). Ion channel regulation may control neurotransmitter release by modifying presynaptic depolarization and Ca2+ dynamics. Neurotransmitter release may also be enhanced through a cGMP-independent action on vesicle cycling (Mothet et al. 1996; Meffert et al. 1996). Nonetheless, it should be noted that our results do not prove a causal relationship between presynaptic current changes and neurotransmitter release (Gally et al. 1990; Hawkins et al. 1998; Snyder 1992) and cannot rule out postsynaptic NO effects. Specific experiments will be needed to further investigate this issue.
The anatomical organization of the cerebellar granule cell layer (Eccles et al. 1967) may have important consequences for NO function. Each mossy fiber terminal contacts numerous granule cells (28 on average) and each granule cell is activated by a few (4 on average) different mossy fibers. By diffusing transcellularly (von Bohlen and Halbach 2002; Wood and Garthwaite 1994), NO released from neighboring granule cells may summate exerting a collective control on the mossy fiber terminal. In turn, membrane depolarization needed to unblock NMDA receptors and release NO should follow synchronous discharge in several mossy fibers (see Armano et al. 2000). Thus the NO signal may influence synaptic plasticity depending on the effective number and location of active granule cells, influencing temporo-spatial processing of mossy fiber discharge and sensori-motor control by the cerebellum. Since NO has also been proposed as an anterograde messenger during LTD at the parallel fiber–Purkinje cell synapse (Casado et al. 2002; Lev-Ram et al. 2002; Shibuki and Okada 1991), granule cells emerge as a central player in cerebellar NO signaling.
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DISCLOSURE |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONDISCLOSUREREFERENCES |
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FOOTNOTES |
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* A. Maffei and F. Prestori contributed equally to this work. 
Address for reprint requests: E. D'Angelo, Department of Physiology and Pharmacology, Section of General Physiology, Pavia University, Via Forlanini 6, 27100 Pavia, Italy (E-mail: dangelo{at}unipv.it).
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REFERENCES |
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; n = 6). SBS did not cause any persistent potentiation, which could be obtained in the same recordings by a subsequent TBS (
; n = 5). In this and following figures, tracings and data points (mean ± SE) are averages of 10 responses.
; n = 5], NO diffusion [10 µM oxy-myoglobin (MbO2);
; n = 5], or guanylyl cyclase activation [10 µM 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-dione (ODQ); 
