Fast NMDA receptor-mediated synaptic currents in neurons from mice lackingthe epsilon 2 (NR2B) subunit

The N-methyl-D-aspartate (NMDA) receptor has been implicated in the formati on of synaptic connections. To investigate the role of the epsilon 2 (NR2B) NMDA receptor subunit, which is prominently expressed during early develop ment, we used neurons from mice lacking this subunit. Although epsilon 2(-/ -) mice die soon after birth, we examined whether NMDA receptor targeting t o the postsynaptic membrane was dependent on the epsilon 2 subunit by rescu ing hippocampal neurons from these mice and studying them in autaptic cultu res. In voltage-clamp recordings, excitatory postsynaptic currents (EPSCs) from epsilon 2(-/-) neurons expressed an NMDA receptor-mediated EPSC that w as apparent as soon as synaptic activity developed. However, compared with wild-type neurons, NMDA receptor-mediated EPSC deactivation kinetics were m uch faster and were less sensitive to glycine, but were blocked by Mg2+ or AP5. Whole cell currents from epsilon 2(-/-) neurons were also more sensiti ve to block by low concentrations of Zn2+ and much less sensitive to the ep silon 2-specific antagonist ifenprodil than wild-type currents. The rapid N MDA receptor-mediated EPSC deactivation kinetics and the pharmacological pr ofile from epsilon 2(-/-) neurons are consistent with the expression of zet a 1/epsilon 1 diheteromeric receptors in excitatory hippocampal neurons fro m mice lacking the epsilon 2 subunit. Thus epsilon 1 can substitute for the epsilon 2 subunit at synapses and epsilon 2 is not required for targeting of NMDA receptors to the postsynaptic membrane.