Target-cell-specific left-right asymmetry of NMDA receptor content in schaffer collateral synapses in epsilon1/NR2A knock-out mice.

Input-dependent left-right asymmetry of NMDA receptor epsilon2 (NR2B) subunit allocation was discovered in hippocampal Schaffer collateral (Sch) and commissural fiber pyramidal cell synapses (Kawakami et al., 2003). To investigate whether this asymmetrical epsilon2 allocation is also related to the types of the postsynaptic cells, we compared postembedding immunogold labeling for epsilon2 in left and right Sch synapses on pyramidal cells and interneurons. To facilitate the detection of epsilon2 density difference, we used epsilon1 (NR2A) knock-out (KO) mice, which have a simplified NMDA receptor subunit composition. The labeling density for epsilon2 but not zeta1 (NR1) and subtype 2/3 glutamate receptor (GluR2/3) in Sch-CA1 pyramidal cell synapses was significantly different between the left and right hippocampus with opposite directions in strata oriens and radiatum; the left to right ratio of epsilon2 labeling density was 1:1.50 in stratum oriens and 1.44:1 in stratum radiatum. No significant difference, however, was detected in CA1 stratum radiatum between the left and right Sch-GluR4-positive (mostly parvalbumin-positive) and Sch-GluR4-negative interneuron synapses. Consistent with the anatomical asymmetry, the amplitude ratio of NMDA EPSCs to non-NMDA EPSCs in pyramidal cells was approximately two times larger in right than left stratum radiatum and vice versa in stratum oriens of epsilon1 KO mice. Moreover, the amplitude of long-term potentiation in the Sch-CA1 synapses of left stratum radiatum was significantly larger than that in the right corresponding synapses. These results indicate that the asymmetry of epsilon2 distribution is target cell specific, resulting in the left-right difference in NMDA receptor content and plasticity in Sch-CA1 pyramidal cell synapses in epsilon1 KO mice.