Platelet-derived growth factor (PDGF) ␤ receptor activation inhibits N-methyl-D-aspartate (NMDA)-evoked currents in hippocampal and cortical neurons via the activation of phospholipase C␥, PKC, the release of intracellular calcium, and a rearrangement of the actin cytoskeleton. In the hippocampus, the majority of NMDA receptors are heteromeric; most are composed of 2 NR1 subunits and 2 NR2A or 2 NR2B subunits. Using NR2B-and NR2A-specific antagonists, we demonstrate that PDGF-BB treatment preferentially inhibits NR2B-containing NMDA receptor currents in CA1 hippocampal neurons and enhances long-term depression in an NR2B subunit-dependent manner. Furthermore, treatment of hippocampal slices or cultures with PDGF-BB decreases the surface localization of NR2B but not of NR2A subunits. PDGF␤ receptors colocalize to a higher degree with NR2B subunits than with NR2A subunits. After neuronal injury, PDGF␤ receptors and PDGF-BB are upregulated and PDGF␤ receptor activation is neuroprotective against glutamate-induced neuronal damage in cultured neurons. We demonstrate that the neuroprotective effects of PDGF-BB are occluded by the NR2B antagonist, Ro25-6981, and that PDGF-BB promotes NMDA signaling to CREB and ERK1/2. We conclude that PDGF␤R signaling, by preferentially targeting NR2B receptors, provides an important mechanism for neuroprotection by growth factors in the central nervous system. N-Methyl-D-aspartate (NMDA)2 receptors are tetrameric, non-selective cation channels composed of two obligate NR1 and two variably expressed NR2 subunits (NR2A-D) although trimeric receptors (2NR1/NR2A/NR2B) are also likely to be present (1). In the hippocampus, NR2A and NR2B are the dominant NR2 forms (2, 3). The majority of synaptic receptors appear to contain the NR2A subunit, whereas NR2B-containing receptors are in greater density extrasynaptically (2, 4, 5), however, this paradigm has recently been challenged (6). Extrasynaptic NMDA receptors or, alternatively, the NR2B-containing NMDA receptors have been directly implicated in the Ca 2ϩ influx that causes excitotoxic cell death (7-10), whereas the synaptic, NR2A-containing receptors have paradoxically been linked to neuroprotection in ischemia (11, 12).Platelet-derived growth factor (PDGF) receptors are highly expressed in CA1 hippocampal neurons and are developmentally important but their functions in the mature CNS are largely unknown (13). There are two major PDGF receptor isoforms (PDGF␣ and PDGF␤ receptors) found in the hippocampus (14). The most intense staining for PDGF␤ receptors is found in the pyramidal cells of the hippocampus (15), whereas PDGF␣ receptors are located primarily on glial cells in this region (16). We have previously demonstrated that the PDGF␤ receptor ligand PDGF-BB inhibits synaptic NMDA receptors at CA1 synapses (17) as well as NMDA-evoked currents of neurons acutely isolated from the CA1 region of the hippocampus (17, 18) or from the prefrontal cortex (19).PDGF␤ receptors have been implicated in neuroprotection following ischemic events (20)...

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