The NMDA (N-methyl-D-aspartate) receptor channel is important for synaptic plasticity, which is thought to underlie learning, memory and development. The NMDA receptor channel is formed by at least two members of the glutamate receptor (GluR) channel subunit families, the GluR epsilon (NR2) and GluR zeta (NR1) subunit families. The four epsilon subunits are distinct in distribution, properties and regulation. On the basis of the Mg2+ sensitivity and expression patterns, we have proposed that the epsilon 1 (NR2A) and epsilon 2 (NR2B) subunits play a role in synaptic plasticity. Here we show that targeted disruption of the mouse epsilon 1 subunit gene resulted in significant reduction of the NMDA receptor channel current and long-term potentiation at the hippocampal CA1 synapses. The mutant mice also showed a moderate deficiency in spatial learning. These results support the notion that the NMDA receptor channel-dependent synaptic plasticity is the cellular basis of certain forms of learning.