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, 17 (7), 2645-51

Nitric Oxide Facilitates Long-Term Potentiation, but Not Long-Term Depression

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Nitric Oxide Facilitates Long-Term Potentiation, but Not Long-Term Depression

P L Malen et al. J Neurosci.

Abstract

Reports that nitric oxide synthase (NOS) inhibition prevents the induction of long-term potentiation (LTP) have been controversial. Recent evidence suggests that NO may help to regulate the threshold for LTP induction. We have tested this hypothesis by examining the effects of stimulus frequency and train duration on synaptic plasticity in the presence of either NO donors or NOS inhibitors. Two different NO donors facilitated LTP induction by stimuli that normally produced only short-term potentiation, whereas NOS inhibitors blocked LTP to stimuli that normally produce small LTP. NO donors facilitated LTP induction even when NMDA receptors were blocked, indicating that NO need not act via NMDA receptors. NO donors and NOS inhibitors were without effect on long-term depression (LTD), suggesting that they act on a distinct potentiating mechanism. Thus, NO could contribute to the establishment of plasticity under physiologically relevant conditions by selectively increasing the probability of LTP induction.

Figures

Fig. 6.
Fig. 6.
The effects of NO donors and NOS inhibitors are on potentiation, but not depression. A, NOS inhibitors have no effect on plasticity induced by 900 pulses at either 1 Hz (which produces large LTD both in control ACSF and in 100 μml-NAME) or 10 Hz (which produces no significant change in either control or inhibited slices). In contrast, the effect of 100 μm NOArg is pronounced and significant on the potentiation normally produced by 900 pulses at 30 Hz in control ACSF. The data for 100 Hz stimulation (asterisk) are taken from Haley et al. (1993) to demonstrate that, at higher frequency, LTP can be independent of NO. B, The effects of NO donors are complementary to those of NOS inhibitors; donors have no effect on stimuli that normally produce LTD but facilitate LTP induction to stimuli that are subthreshold in control ACSF. NO donors do not produce further facilitation when normally suprathreshold tetani (e.g., theta bursts) are delivered.
Fig. 1.
Fig. 1.
H2NOH facilitates LTP induction. A 25-pulse stimulus train delivered at either 10 or 50 Hz (A) produced only short-term potentiation in slices bathed in normal ACSF (open symbols). In the presence of 200 μm H2NOH (filled symbols), both 10 and 50 Hz HFS produced potentiation that was still significant after 60 min. H2NOH was washed in 20 min before tetanus, and washed out 5 min after tetanus (horizontal line in A). A 25-pulse stimulus at 50 Hz was delivered to nine additional slices in control ACSF (B). As in A, responses returned to baseline after 60 min. H2NOH was washed onto these same slices for 20 min (horizontal line in B), followed by repetition of the 50 Hz HFS, which this time produced significant enhancement of the field EPSP slope, which lasted at least 60 min after the tetanus. Error bars in all figures represent SEM.
Fig. 2.
Fig. 2.
The specific NO donor SNOC facilitates LTP induction. The application of 100 μm SNOC has an effect identical to that of H2NOH. The 25 pulses delivered at 50 Hz produced significant potentiation in the presence of SNOC prepared freshly and stored on ice. SNOC that had been allowed to degrade to cystine by leaving the SNOC stock solution overnight at room temperature had a less pronounced effect on tetanus, producing an enhancement that was not significantly greater than control 50 Hz HFS 60 min after tetanus.
Fig. 3.
Fig. 3.
AP5 does not block SNOC-facilitated LTP. Tetanic stimulation consisting of 25 pulses delivered at 50 Hz was delivered to slices bathed in 100 μmdl-AP5. Ten minutes after tetanus, AP5 plus either 100 μm SNOC (A) or SNOC depleted of NO by maintaining at room temperature for at least 24 hr (B) was washed in. Twenty minutes later (30 min after the first tetanus), slices were tetanized again. SNOC was washed out 5 min after the second tetanus. Significant potentiation was recorded only in the presence of SNOC.
Fig. 4.
Fig. 4.
H2NOH has no effect on LTD. Slices taken from young rats and bathed in either control ACSF (open symbols) or ACSF containing 200 μmH2NOH (filled symbols) were given stimuli designed to produce either large LTD (600 pulses delivered at 3 Hz, A) or minimal LTD (100 pulses at 1 Hz,B). The addition of H2NOH to the bath had no effect on the plasticity induced by these stimuli.
Fig. 5.
Fig. 5.
NOS inhibitors prevent LTP induction by prolonged stimulation at 30 Hz. Delivery of 900 pulses at 30 Hz in control ACSF (open circles) produces LTP of the field EPSP slope. The same tetanus delivered in the presence of 100 μm NOArg leads to only short-term potentiation. Slices were exposed to NOArg for at least 30 min before tetanus and throughout the post-tetanus measurement period.

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