Target-cell-specific left-right asymmetry of NMDA receptor content in Schaffer collateral synapses in ∈1/NR2A knock-out mice

Input-dependent left-right asymmetry of NMDA receptor epsilon 2 (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 epsilon 2 allocation is also related to the types of the postsynaptic cells, we compared postembedding immunogold labeling for epsilon 2 in left and right Sch synapses on pyramidal cells and interneurons. To facilitate the detection of epsilon 2 density difference, we used epsilon 1 (NR2A) knock-out (K0) mice, which have a simplified NMDA receptor subunit composition. The labeling density for epsilon 2 but not zeta 1 (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 epsilon 2 labeling density was 1:1.50 in stratum oriens and 1.44:1 in stratum radiatum. Nosignificant 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 epsilon 1 K0 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 epsilon 2 distribution is target cell specific, resulting in the left-right difference in NMDA receptor content and plasticity in Sch-CA1 pyramidal cell synapses in epsilon 1 K0 mice.