Integrated regulation of signal coding and plasticity by NMDA receptors at a central synapse

The role of NMDA and non-NMDA glutamate receptors in long-term potentiation has been intensely investigated, yet recent evidence on the dynamics of synaptic depolarization suggests that the original view should be extended. NMDA receptor-mediated currents, apart from their Ca²⁺ permeability, show a marked voltage dependence, consisting of current increase and slowdown during membrane depolarization. During high-frequency synaptic transmission, NMDA current increase and slowdown are primed by non-NMDA receptor-dependent depolarization and proceed regeneratively. Thus, NMDA receptors make a decisive contribution to membrane depolarization and spike-firing. From the data obtained at the messy fiber-granule cell synapse of the cerebellum, we propose that the electrogenic role of NMDA receptors is functional to LTP induction. Moreover, during LTP, both NMDA and non-NMDA receptor currents are potentiated, thus establishing a feed-forward mechanism that ultimately enhances spike firing. Thus, NMDA receptors exert an integrated control on signal coding and plasticity. This mechanism may have important implications for information processing at the cerebellar messy fiber-granule cell relay.