Electrophysiological analysis of NMDA receptor subunit changes in the aging mouse cortex.

NMDA receptors play an important role in memory processes and plasticity in the brain. We have previously demonstrated a significant decrease in NMDARepsilon2 subunit mRNA and protein with increasing age in the C57Bl/6 mouse frontal cortex. In the present study, two-electrode voltage clamp electrophysiology on Xenopus oocytes injected with total RNA harvested from the frontal cortex of young and old C57Bl mice was used to detect changes in receptor composition during aging. Ifenprodil concentration-response curves, magnesium current-voltage curves, and single channel conductances were determined for native receptors. In addition, ifenprodil and magnesium curves were generated for recombinant NMDA receptors of varying subunit ratios. Ifenprodil dose-response curves for all receptors were biphasic. The low affinity component of the curve increased slightly with age, while the high affinity population decreased, mimicking recombinant receptors with decreasing levels of epsilon2. A decrease in maximal current was also observed in aged animals with decreased levels of epsilon2, although single channel conductances were identical between young and old mice. In addition, an increase in sensitivity to magnesium was observed for receptors from older animals. Results are consistent with the interpretation that the epsilon2 subunit is reduced in older mouse frontal cortex. A change in NMDA receptor subunit composition could influence memory processes during aging.