cAMP-dependent long-term potentiation of nitric oxide release from cerebellar parallel fibers in rats

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 (LTP(NO)) by 36 ± 3% (n = 15) after tetanic PF stimulation. Induction of LTP(NO) was not affected by Glu receptor antagonists. NO release from PFs was also potentiated by L-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 LTP(NO). 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 LTP(NO). These data indicate that neural NO release is under activity-dependent control, just as synaptic transmitter release is. LTP(NO) might 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 LTP(NO).