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, 21 (10), 3515-20

Retrograde Carbon Monoxide Is Required for Induction of Long-Term Potentiation in Rat Superior Cervical Ganglion

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Retrograde Carbon Monoxide Is Required for Induction of Long-Term Potentiation in Rat Superior Cervical Ganglion

K A Alkadhi et al. J Neurosci.

Abstract

Carbon monoxide (CO), produced in the body by the enzyme heme oxygenase (HO), has been suggested as a retrograde synaptic messenger with a prominent role in the long-term potentiation (LTP) of certain areas of the brain. LTP of sympathetic ganglia is 5-HT(3) receptor-dependent and has been shown to require nitric oxide for the maintenance, but not for the induction, phase. We investigated the possibility of CO being required for the induction of ganglionic LTP. Pretreatment of rat isolated superior cervical ganglia with oxyhemoglobin (25-100 microm) completely blocked LTP. In the same ganglia, prolonged washout of oxyhemoglobin did not uncover any potentiation of the compound action potential. Oxyhemoglobin had no significant effect on the maintenance phase in ganglia with established LTP. Pretreatment of ganglia with the HO inhibitor zinc protoporphyrin-IX (ZnPP) (10 microm) completely and irreversibly prevented the expression of tetanus-evoked LTP. However, in the same ganglia, after superfusion of CO in the presence of ZnPP, tetanic stimulation readily evoked LTP. No effect was seen on the maintenance phase when ZnPP was superfused on ganglia with established LTP. Pretreatment of ganglia with the 5-HT(3) receptor antagonist ondansetron (0.4 microm) alone completely and irreversibly blocked LTP. However, in the presence of CO, ondansetron did not block LTP. These results suggest that activation of 5-HT(3) receptors may be involved in the production of CO. The results also suggest that CO, probably originating outside the presynaptic nerve terminal, is involved in the induction of LTP.

Figures

Fig. 1.
Fig. 1.
Effect of the membrane-impermeable, NO–CO scavenger oxyhemoglobin on LTP of the rat SCG. A, In ganglia pretreated with Hb (100 μm; solid horizontal line), tetanus failed to induce LTP. No significant recovery of LTP was seen on washout of oxyhemoglobin 40 min after tetanus. Each point is the mean ± SEM from 10 ganglia. When not shown, error bars are within thesymbols. Inset, Records of CAPs from a representative ganglion taken at times indicated on the graph. Calibration: 0.4 mV, 20 msec. Points between thetwo asterisks are not significantly different from baseline. B, Superfusion of oxyhemoglobin on ganglia during the maintenance phase of established LTP produced no significant effect on this phase of LTP. Each point is the mean ± SEM from seven ganglia.
Fig. 2.
Fig. 2.
Washout of oxyhemoglobin restored the ability of tetanus to generate LTP. The presence of Hb (25 μm) prevented tetanus-induced LTP (arrowhead 1). However, after washout of oxyhemoglobin, a second tetanus (arrowhead 2) readily evoked LTP. Each point is the mean ± SEM from five ganglia. Points between thetwo asterisks are not significantly different from baseline.
Fig. 3.
Fig. 3.
Removal of the NO synthase inhibitorl-NOARG resulted in reversal of inhibition of ganglionic LTP. A, LTP blocked by l-NOARG (50 μm; solid horizontal line) was fully restored when the inhibitor was washed out. Each pointis the mean ± SEM from eight ganglia. B, Superfusion of l-NOARG (50 μm; solid horizontal line) on established LTP resulted in complete, but reversible, inhibition of ganglionic transmission enhancement.Inset, Records of CAPs from a representative ganglion taken at times indicated on the graph. Calibration: 0.4 mV, 20 msec. Each point is the mean ± SEM from four ganglia.Points between the two asterisks are not significantly different from baseline in both series.
Fig. 4.
Fig. 4.
Effect of inhibition of the CO-generating enzyme HO2 on ganglionic LTP. A, Superfusion of the HO2 inhibitor ZnPP (10 μm; solid horizontal line) before tetanus completely and irreversibly blocked expression of LTP. Inset, Records of CAPs from a representative ganglion taken at times indicated on the graph. Calibration: 0.4 mV, 20 msec. Each point is the mean ± SEM from 13 ganglia. B, ZnPP produced no significant effect on ganglionic transmission when superfused during the maintenance phase of established LTP. Each point is the mean ± SEM from four ganglia.
Fig. 5.
Fig. 5.
The presence of CO renders ZnPP ineffective in blocking ganglionic LTP. A, ZnPP (solid horizontal line) given before tetanus (arrowhead 1) completely blocked ganglionic LTP. In the same ganglia, after superfusion of CO solution (0.2–2.0 μm;solid horizontal line) and in the presence of ZnPP, a second tetanus (arrowhead 2) evoked a robust LTP. Eachpoint is the mean ± SEM from five ganglia.B, A similar series in which two tetani were used in the presence of ZnPP but without CO is shown for comparison. Eachpoint is the mean ± SEM from three ganglia. After each tetanus, points between the two asterisks are not significantly different from baseline in both series.
Fig. 6.
Fig. 6.
The 5-HT3 receptor antagonist ondansetron did not block ganglionic LTP in the presence of CO.A, Ondansetron (0.4 μm; solid horizontal line) completely and irreversibly blocked LTP of the SCG. Each point is the mean ± SEM from four ganglia. B, In the presence of CO (0.2–2.0 μm; solid horizontal line), ondansetron failed to inhibit LTP. Each point is the mean ± SEM from four ganglia.

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