ACTIVITY DIFFERENTIALLY REGULATES THE SURFACE EXPRESSION OF SYNAPTIC AMPA AND NMDA GLUTAMATE RECEPTORS

Distinct subtypes of glutamate receptors often are colocalized at indi vidual excitatory synapses in the mammalian brain get appear to subser ve distinct functions. To address whether neuronal activity may differ entially regulate the surface expression at synapses of two specific s ubtypes of ionotropic glutamate receptors we epitope-tagged an AMPA lp ha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) receptor subuni t (GluR1) and an NMDA (N-methyl-D-aspartate) receptor subunit (NR1) on their extracellular termini and expressed these proteins in cultured hippocampal neurons using recombinant adenoviruses, Both receptor subt ypes were appropriately targeted to the synaptic plasma membrane as de fined by colocalization with the synaptic vesicle protein synaptophysi n. Increasing activity in the network of cultured cells by prolonged b lockade of inhibitory synapses with the gamma-aminobutyric acid type A receptor antagonist picrotoxin caused an activity-dependent and NMDA receptor-dependent decrease in surface expression of GluR1, but not NR 1, at synapses, Consistent with this observation identical treatment o f noninfected cultures decreased the contribution of endogenous AMPA r eceptors to synaptic currents relative to endogenous NMDA receptors, T hese results indicate that neuronal activity can differentially regula te the surface expression of AMPA and NMDA receptors at individual syn apses.