Extracellular glutamate diffusion determines the occupancy of glutamate receptors at CA1 synapses in the hippocampus

Following exocytosis at excitatory synapses in the brain, glutamate binds t o several subtypes of postsynaptic receptors. The degree of occupancy of AM PA and NMDA receptors at hippocampal synapses is, however, not known. One a pproach to estimate receptor occupancy is to examine quantal amplitude fluc tuations of postsynaptic signals in hippocampal neurons studied in vitro. T he results of such experiments suggest that NMDA receptors at CA1 synapses are activated not only by glutamate released from the immediately apposed p resynaptic terminals, but also by glutamate spillover from neighbouring ter minals. Numerical simulations point to the extracellular diffusion coeffici ent as a critical parameter that determines the extent of activation of rec eptors positioned at different distances from the release site. We have sho wn that raising the viscosity of the extracellular medium can modulate the diffusion coefficient, providing an experimental tool to investigate the ro le of diffusion in activation of synaptic and extrasynaptic receptors. Whet her intersynaptic cross-talk mediated by NMDA receptors occurs in vivo rema ins to be determined. The theoretical and experimental approaches described here also promise to shed light on the roles of metabotropic and kainate r eceptors, which often occur in an extrasynaptic distribution, and are there fore positioned to sense glutamate escaping from the synaptic cleft.