| Glutamate receptors are heteromultimeric channels that have been implicated in the refinement of synaptic connectivity during development, and the pathogenesis of post-ischemic neuronal cell death. This work examines the role of glutamate receptors in these processes.; The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate subclass of glutamate receptors (AMPARs) is comprised of a combination of four subunits termed GluR1-4, each of which exists as a ‘flip’ or ‘flop’ splice variant. To determine whether the subunit composition, and hence the functional properties, of AMPARs affects the vulnerability of neurons to excitotoxicity, we generated transgenic mice overexpressing the GluR2-flip subunit. Cultured neurons from transgenic mice were more susceptible to the toxic effect of glutamate than wild-type neurons. Moreover, transgenic mice subjected to focal ischemia sustained larger infarctions than wildtype controls. This demonstrates the crucial role of AMPARs in the pathogenesis of post-ischemic neuronal death.; The N-methyl-D-aspartate (NMDA) subclass of glutamate receptors (NMDARs) is comprised of an essential NR1 subunit and at least one NR2 subunit. Developmental regulation of NMDAR subunit expression may be important in synapse formation. A developmentally regulated putative glutamate receptor subunit, NMDAR-L (also called χ-1) was recently isolated for its homology to NMDARs. In this study, we have identified NMDAR-L as the first member of a novel subfamily of NMDARs, and renamed it NR3A.; We found that NR3A protein forms a stable complex with NR1 and NR2 subunits when expressed in cultured mammalian cells, and associates with NR1 and NR2 in brain extracts. Furthermore, like NR1 and NR2s, NR3A was enriched in the postsynaptic density fraction. Thus NR3A is part of the NMDAR complex in the early postnatal brain.; To identify its potential physiological roles, we generated mice deficient in NR3A. NMDA-evoked currents were larger in young NR3A–/– cortical neurons than in wild-type neurons. Moreover, the spine density and morphology were altered in layer IV-V neurons in NR3A-deficient mice. These data indicate that NR3A regulates NMDAR activities in vivo and plays a critical role in the development of cerebrocortical synaptic structures. |
