Developmental loss of miniature N -methyl- d -aspartate receptor currents in NR2A knockout mice

• DOI: 10.1073/pnas.0335786100
• Publication Date: 2003-02-04T17:24:41Z
• Authors: Matthew Townsend; Akira Yoshii; M. Mishina; Martha Constantin...
• Keywords: Mice, Knockout; 0301 basic medicine; Binding Sites; Time Factors; Blotting, Western; Intracellular Signaling Peptides and Proteins; Membrane Proteins; Nerve Tissue Proteins; Models, Biological; Precipitin Tests; Receptors, N-Methyl-D-Aspartate; Electrophysiology; Mice, Inbred C57BL; Kinetics; Mice; 03 medical and health sciences; Animals; Calcium; Disks Large Homolog 4 Protein; Guanylate Kinases; Protein Binding

The N -methyl- d -aspartate (NMDA) glutamate receptor (NMDAR), long implicated in developmental plasticity, shows decay time kinetics that shorten postnatally as NR2A subunits are added to the receptor. Neither the mechanism nor immediate effect of this change is known. We studied developing NMDAR currents by using visual neurons in slices from NR2A knockout (NR2AKO) and WT mice. Both strains show increased dendritic levels of synaptic density scaffolding protein PSD-95 with age. Dendritic levels of NR2A increased at the same time in WT and immunoprecipitated with PSD-95. PSD-95/NMDAR binding was significantly decreased in the NR2AKO. Moreover, NMDAR miniature currents (minis) were lost and rise times of NMDAR evoked currents increased in mutant mice. Age-matched WT cells showed NR2A-rich receptors predominating in minis, yet slow NR2B mediated currents persisted in evoked currents. Disrupting photoreceptor activation of retinal ganglion cells eliminated increases in PSD-95 and NR2A in superior collicular dendrites of WT mice and slowed the loss of miniature NMDAR currents in NR2AKOs. These data demonstrate that NMDARs that respond to single quantal events mature faster during development by expressing the NR2A subunit earlier than NMDARs that respond to evoked release. We hypothesize that NR2A-rich NMDARs may be localized to the center of developing synapses by an activity-dependent process that involves the targeting of PSD-95 to the postsynaptic density. Neonatal receptors become restricted to perisynpatic or extrasynaptic sites, where they participate primarily in evoked currents.