cAMP-Dependent Long-Term Potentiation of Nitric Oxide Release from Cerebellar Parallel Fibers in Rats

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Abstract
Nitric Oxide (NO) is released from parallel fibers (PFs) after PF stimulation. NO–cGMP signaling is essential for long-term depression (LTD) in cerebellar PF–Purkinje cell synapses, which also exhibit presynaptic long-term potentiation (LTP) after tetanic PF stimulation. This LTP is dependent on cAMP but not NO–cGMP signaling. In this study, we analyzed long-term changes of NO release from PFs in rat cerebellar slices using electrochemical NO probes. Repetitive PF stimulation at 10 Hz for 2 sec elicited a transient increase in NO concentration (2.2 ± 0.1 nm; mean ± SEM;n= 116). This NO release exhibited long-term potentiation (LTPNO) by 36 ± 3% (n= 15) after tetanic PF stimulation. Induction of LTPNOwas not affected by Glu receptor antagonists. NO release from PFs was also potentiated byl-Arg (ARG) (100 μm), forskolin (50 μm), and 8-bromo-cAMP (Br-cAMP) (1 mm) but not by 1,9-dideoxyforskolin (50 μm), a biologically inactive analog of forskolin. The potentiation induced by forskolin was significantly suppressed by H89 (10 μm), a blocker of cAMP-dependent protein kinase. The potentiation induced by forskolin, but not that induced by Arg, interfered with LTPNO. H89 (10 μm) and KT5720 (1 μm), another blocker of cAMP-dependent protein kinase, but not KT5823 (300 nm), a blocker of cGMP-dependent protein kinase, significantly suppressed LTPNO. These data indicate that neural NO release is under activity-dependent control, just as synaptic transmitter release is. LTPNOmight play a role in cross talk between presynaptic and postsynaptic plasticity by facilitating NO–cGMP-dependent postsynaptic LTD after induction of cAMP-dependent presynaptic LTP and LTPNO.