Length of postovariectomy interval and age, but not estrogen replacement, regulate N-methyl-D-aspartate receptor mRNA levels in the hippocampus of female rats

Estrogens and N-methyl-D-aspartate (NMDA) receptors regulate multiple aspec ts of morphological and functional plasticity in young animals. For example , estrogens increase spine density in the hippocampus, and NMDA antagonists block these effects. Few studies have examined the effects of age, postova riectomy interval, and duration of estrogen replacement in the hippocampus and more specifically on NMDA receptor subunits. Therefore, the present stu dy was designed to investigate the effects of short- and long-term estrogen replacement or deprivation on mRNA levels of three NMDA receptor subunits, NR1, NR2A, and NR2B, in the hippocampus of aging female Sprague-Dawley rat s. Young (3- to 4-month-old) and middle-aged (12- to 13-month-old) rats wer e ovariectomized for 1 month and then treated with estrogen or vehicle for either 2 days or 2 weeks. Another set of middle-aged and aged (24-to 25-mon th-old) animals were ovariectomized for 6 months and treated with estrogen or vehicle for 2 days or 2 weeks. RNase protection assay was used to assess changes in the NMDA receptor subunit mRNA levels. Our results demonstrated significant effects of age and length of ovariectomy on NMDA receptor mRNA levels, with little effect of the estrogen status of the animals on these parameters. The largest effect was seen for the length of the postovariecto my interval, with the results demonstrating that rats with a short-term ova riectomy have substantially higher NMDA receptor subunit mRNA levels than a nimals with long-term ovariectomy. The most dramatic effects of aging were seen for NR1 and NR2B mRNAs in ventral hippocampus, with large age-related increases. These data suggest that age and duration of ovariectomy impact N MDA receptor mRNA levels in the hippocampus, potentially affecting the stoi chiometry and/or function of these receptors. These findings have important implications for postmenopausal or hysterectomy/oophorectomy estrogen depl etion and replacement in humans. (C) 2001 Academic Press.