ROLES OF ESTRADIOL AND PROGESTERONE IN REGULATION OF HIPPOCAMPAL DENDRITIC SPINE DENSITY DURING THE ESTROUS-CYCLE IN THE RAT

We have previously shown that the density of dendritic spines on hippo campal CA1 pyramidal cells is dependent on circulating estradiol and p rogesterone and fluctuates naturally during the 5 day estrous cycle in the adult rat. To date, however, no detailed characterization of the roles that these hormones play in regulation of spine density has been made. In order to determine the time courses and extent of the effect s of estradiol and progesterone on dendritic spine density, we have an alyzed the density of dendritic spines on the lateral branches of the apical dendritic tree of Golgi-impregnated CA1 hippocampal pyramidal c ells in several experiments. In summary, our findings included the fol lowing: (1) Following ovariectomy, circulating estradiol is undetectab le within 24 hours; however, spine density decreases gradually over a 6 day period. (2) Spine density does not decrease any further up to 40 days following ovariectomy. (3) Treatment with estradiol alone can re verse the ovariectomy-induced decrease in spine density. (4) Spine den sity begins to increase within 24 hours following estradiol benzoate i njection in an ovariectomized animal, peaks at 2 and 3 days, then grad ually decreases over the next 7 day period. (5) Although free estradio l is metabolized more rapidly than estradiol benzoate, there is no dif ference in the rate of decrease in spine density following injection o f either form. (6) Progesterone has a biphasic effect on spine density in that progesterone treatment following estradiol initially increase s spine density for a period of 2 to 6 hours but then results in a muc h sharper decrease than is observed following estradiol alone. By 18 h ours following progesterone treatment, spine density is decreased near ly to 6 day ovariectomy values. (7) Treatment of intact rats with the progesterone receptor antagonist, RU 486, during the proestrus phase o f the estrous cycle inhibits the proestrus to estrus drop in spine den sity. These findings account for both the gradual increase and rapid d ecrease in spine density which we have previously observed during the estrous cycle and indicate that progesterone in particular may be an i mportant factor in the regulation of rapid morphologic changes which o ccur naturally in the adult brain. (C) 1993 Wiley-Liss, Inc.