Differential Astrocyte-supplied NMDAR Co-Agonist for CA1 versus Dentate Gyrus Long-term Potentiation

Abstract In the hippocampus, there is a region and synapse-specific N-methyl-D-aspartate receptor (NMDAR) co-agonist preference for induction of long-term potentiation (LTP). Schaffer collateral (SC)-CA1 synapses, enriched in GluN2A-containing NMDARs, favor D-serine, while medial perforant path (MPP) to dentate gyrus (DG) synapses that are rich in GluN2B-containing NMDARs prefer glycine for LTP induction. This study investigated the role of astrocytes in providing these co-agonists. We confirmed in rat hippocampal slices that exogenous D-serine (10 µM) is sufficient to restore LTP at SC-CA1 synapses blocked under astrocyte calcium (Ca 2+ ) -clamp conditions, consistent with previous findings. However, exogenous glycine (10 μM) also rescued the LTP. In contrast, at MPP-DG synapses, 100 µM exogenous glycine, but not 10 µM nor 100 µM D-serine, restored the LTP blocked by astrocyte Ca 2+ -clamping. Our findings support the view that, as for serine in CA1, astrocytes are the cellular source of the glycine required for LTP induction at MPP-DG synapses.