An NMDA receptor/nitric oxide cascade in presynaptic parallel fiber-Purkinje neuron long-term potentiation

Plasticity of synaptic transmission between parallel fiber (PF) and Purkinje neurons (PNs) is widely accepted as a cellular model for certain forms of cerebellar learning. Whereas the signaling cascades involved in postsynaptically expressed bidirectional long-term changes at PF-PN synapses are well investigated, data on presynaptically expressed long-term potentiation (LTP) are incomplete and controversial. Here we used transgenic mice that express a fluorescent protein Ca²⁺ sensor in PFs to demonstrate LTP of PF presynaptic Ca²⁺ transients after PF stimulation with 120 pulses at 4 Hz. Potentiation of the presynaptic Ca²⁺ transients correlated with the expression of simultaneously recorded LTP of PF-PN synaptic transmission and was suppressed by a protein kinase A inhibitor. Moreover, this presynaptically expressed form of LTP clearly required activation of an NMDA receptor/nitric oxide pathway, in contrast with the majority of previous reports. Blockade of NMDA receptors did not affect the PF Ca²⁺ transients induced during 4 Hz stimulation, indicating that the NMDA receptors required for the induction of presynaptic PF LTP are not localized in PFs.