Nitric oxide is required for the induction and heterosynaptic spread of long-term potentiation in rat cerebellar slices

1. In the cerebellar cortex, brief, 8 Hz activation of parallel fibres (PFs ) induces a cyclic adenosine 3'5'-monophosphate (cAMP) and protein kinase A (PKA)-dependent form of long-term potentiation between PFs and Purkinje ce lls. 2. With 10 mM BAPTA in the recording pipette, potentiation evoked by raised frequency stimulation(RFS) to one of two, synaptically independent, PF inp uts to the same Purkinje cell did not remain input specific but consistentl y spread to synapses that did not receive RFS, up to the maximum distance t ested of 168 mum. 3. LTP at activated and non-activated sites was accompanied by a decrease i n paired pulse facilitation (PPF). The PKA inhibitor H-89 blocked both of t hese effects. Inhibition of nitric oxide synthase (NOS), either by 7-nitro- indazole (7-NI) or N-G-nitro-L-arginine methyl ester (L-NAME), completely p revented heterosynaptic potentiation and associated reduction in PPF. LTP a t distant synapses was selectively prevented by the nitric oxide scavenger 2-(4carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (cPTIO). I nhibition of soluble guanylate cyclase or protein kinase G had no effect on either pathway. 4. Synaptic potentiation at PF-PC synapses, induced by the adenylate cyclas e activator forskolin, was also prevented by inhibition of NOS. Forskolin-i nduced increases in mEPSC frequency were similarly prevented by NOS inhibit ion and mimicked by the NO donor spermine NONOate. 5. These results are consistent with the notion that heterosynaptic potenti ation is of pre-synaptic origin and dependent upon activation of cAMP/PKA a nd NO. Moreover, they suggest that cAMP/PKA activation stimulates NO produc tion and this diffusible messenger facilitates presynaptic transmitter rele ase at synapses within a radius of upwards of 150 mum, through a mechanism that does not involve cGMP.