Art - Ottersen (Y)

AMPA and NMDA receptors are the major classes of ionotropic receptors in central glutamatergic synapses1–3. There is now strong evidence from high-resolution immunogold analyses that both receptors are concentrated opposite the presynaptic active zone in a membrane domain that coincides precisely with the postsynaptic density3–9. However, it is not known what factors determine relative density of AMPA and NMDA receptors at synapses at which the two receptors are colocalized. The physiological significance of the ratio between these receptors is illustrated by the extreme cases of zero or infinite values; the first of these extremes should produce synapses that are silent at normal resting potentials10–12, whereas the latter would be incompatible with NMDA receptor-dependent synaptic plasticity13. Here we explore the hypothesis that synaptic size is an important factor determining the ratio of AMPA to NMDA receptors at the synapse. We focused our study on Schaffer collateral–commissural synapses. These synapses show considerable size heterogeneity14,15 and sustain NMDA receptor-dependent long-term potentiation (LTP)13,16,17. Moreover, some SCC synapses contain few or no AMPA receptors, and the number of AMPA receptors increases with increasing synapse size8. However, it is unknown whether the NMDA receptors show the same dependence on synapse size. Using a highly sensitive postembedding immunogold procedure5, we show that AMPA and NMDA receptors are differentially expressed in SCC synapses and that the ratio between the two receptors increases linearly with synapse diameters above 180 nm. We also demonstrate that the subpopulation of SCC synapses devoid of detectable AMPA-receptor immunoreactivity8,18 does contain NMDA receptors, thus conforming to properties expected for ‘silent synapses’10–12.