Endogenous nitric oxide release required for long-term synaptic depression in the cerebellum

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Abstract
Conjunctive stimulation of climbing and parallel fibres in the cerebellum evokes a long-term depression of parallel-fibre Purkinje-cell transmission, a phenomenon implicated as the cellular mechanism for cerebellar motor learning. It is suspected that the increase in cyclic GMP concentration that occurs after activation of climbing fibres is required to evoke long-term depression. Excitatory amino acids are known to cause the release of nitric oxide (NO), resulting in elevation of the cGMP level in the cerebellum. Here we report that endogenous NO is released after stimulation of climbing fibres, that long-term depression evoked by conjunctive stimulation of parallel and climbing fibres is blocked by haemoglobin (which strongly binds NO) or L-NG-monomethyl-arginine (an inhibitor of NO synthase), and that exogenous NO or cGMP can substitute for the stimulation of climbing fibres to cause long-term depression in rat cerebellar slices. These results demonstrate that the release of endogenous NO is essential for the induction of synaptic plasticity in the cerebellum.