The neurotoxin N-methyl-D-aspartate was used to induce selective bilateral neuronal loss in the entorhinal cortex, in order to model one aspect of the neurodegeneration observed in Alzheimer's disease, Down's syndrome and aging. Lesioned, sham-lesioned and intact control rats learned a reference memory task involving a brightness discrimination for water reward. Rats were trained over 1 week until reaching criteria and tested for retention after a 10-day interval. Lesioned rats showed impaired retention compared to shams and controls, but were able to reacquire the task. Anatomical analysis confirmed excitotoxic lesions of the entorhinal cortex, and showed collateral sprouting of acetylcholinesterase-stained fibers into the outer molecular layer of the dentate gyrus, indicating denervation plasticity in the hippocampus. This functional anatomical study of the entorhinal cortex demonstrates the importance of the entorhinal cortex in memory retention, and raises the possibility that functional deficits in certain neurodegenerative diseases may be modeled by partial neuronal loss in the entorhinal cortex.