Long-trace interval eyeblink conditioning is impaired in mutant mice lacking the NMDA receptor subunit epsilon 1

To elucidate the role of the N-methyl-D-aspartate (NMDA) -type glutamate receptor subunit epsilon 1 (GluR epsilon 1) in classical eyeblink conditioning, delay and trace eyeblink conditioning were investigated in GluR epsilon 1-null mutant mice. In delay conditioning and short-trace interval conditioning with a trace interval of 250 ms, GluR epsilon 1 mutant mice attained a normal level of the conditioned response (CR), although acquisition was a little slower than in wild-type mice. In contrast, GluR epsilon 1 mutant mice exhibited severe impairment of the attained level of the CR and disturbed temporal pattern of CR expression in trace conditioning with a longer trace interval of 500 ms. These findings indicate that GluR epsilon 1 is essential for long-trace interval eyeblink conditioning. The impairments of the associative learning with a long temporal separation between the conditioned and unconditioned stimuli observed in the GluR epsilon 1 mutant mice could be attributed to an impairment of hippocampal long-term potentiation in this line of mutant mice.