LONG-TERM DEPRESSION IN RAT CEREBELLUM REQUIRES BOTH NO SYNTHASE AND NO-SENSITIVE GUANYLYL CYCLASE

Long-term depression (LTD) of synaptic transmission between parallel f ibres and Purkinje cells is a well-known example of synaptic plasticit y taking place in the cerebellum. Nitric oxide (NO) has been implicate d in synaptic plasticity in other brain areas, but its function in cer ebellar LTD is controversial. Even when an involvement is suggested, t he NO signal transduction pathway is unclear. One candidate is the cyc lic GMP-synthesizing enzyme, soluble guanylyl cyclase, whose activity in the brain and elsewhere is powerfully stimulated by NO. By recordin g intracellularly from Purkinje cells in cerebellar slices, we demonst rate that blockade of NO synthase completely inhibits LTD induced by p airing parallel fibre stimulation with postsynaptic Ca2+ spike firing. LTD was also blocked by intracellular application of 1H-[1,2,4]oxadia zolo[4,3-a]quinoxalin-1-one, a recently identified potent and selectiv e inhibitor of soluble guanylyl cyclase. These findings indicate that soluble guanylyl cyclase is required for cerebellar LTD and suggest th at this enzyme, located within Purkinje cells, transduces the NO signa l in this form of synaptic plasticity.