SYNERGIES AND COINCIDENCE REQUIREMENTS BETWEEN NO, CGMP, AND CA2-TERMDEPRESSION( IN THE INDUCTION OF CEREBELLAR LONG)

Parallel fiber synapses onto Purkinje neurons in acute cerebellar slic es undergo long-term depression (LTD) when presynaptic activity coinci des with postsynaptic depolarization. These electrical inputs can be r espectively replaced by nitric oxide (NO) and Ca2+ photolytically rele ased inside the Purkinje neuron,: showing that these two messengers ar e sufficient for LTD induction. NO acts via cGMP production because in hibitors of guanylate cyclase prevent LTD but can be circumvented by p hotoreleased cGMP combined with Ca2+ elevation. Three inhibitors of cG MP-dependent protein kinase, Rp-8Br-PET-cGMPS, KT5823, and a novel pse udosubstrate peptide, all block LTD. LTD induction permits <10 ms gap between NO release and Ca2+ elevation, whereas 200-300 ms is allowed b etween uncaged cGMP and Ca2+ increase. This surprising difference in t iming precision can be explained either by tighter localization and fa ster decay of cGMP when generated by NO rather than uncaging, or by tw o independent coincidence detectors in series.