Effects of Androgens and Estradiol on Spine Synapse Formation in the Prefrontal Cortex of Normal and Testicular Feminization Mutant Male Rats

Abstract

Recent studies suggest that, in female monkeys and rats, estrogens elicit dendritic spine synapse formation in the prefrontal cortex, an area that, similar to the hippocampus, plays a critical role in cognition. However, whether gonadal hormones induce synaptic remodeling in the male prefrontal cortex remains unknown. Here we report that gonadectomy reduced, whereas administration of 5␣-dihydrotestosterone or estradiol-benzoate to castrated male rats increased, the number of medial prefrontal cortical (mPFC) spine synapses, with estradiol-benzoate being less effective than 5␣-dihydrotestosterone. To investigate whether the androgen receptor contributes to the mediation of these changes, we compared the response of testicular feminization mutant (Tfm) male rats to that of wild-type animals. The number of mPFC spine synapses in gonadally intact Tfm rats and 5␣-dihydrotestosterone-treated castrated Tfm males was considerably reduced compared to intact wild-type animals, whereas the synaptogenic effect of estradiol-benzoate was surprisingly enhanced in Tfm rats. These data are consistent with the hypothesis that remodeling of spine synapses in the prefrontal cortex may contribute to the cognitive effect of gonadal steroids. Our findings in Tfm animals indicate that androgen receptors may mediate a large part of the synaptogenic action of androgens in the mPFC of adult males. However, because this effect of 5␣-dihydrotestosterone is not completely lost in Tfm rats, additional mechanisms may also be involved. (Endocrinology 148: 1963(Endocrinology 148: -1967(Endocrinology 148: , 2007 I T IS WELL DOCUMENTED that gonadal steroid hormones significantly influence cognitive performance in both humans and laboratory animals (1). Recent studies also suggest that remodeling and subsequent stabilization of dendritic spine synapses may represent a mechanism by which new memories are made and stored (2, 3). Consequently, it is believed that remodeling of spine synapses significantly contributes to the cognitive effect of gonadal hormones. Indeed, pioneering studies from Woolley and McEwen (4) have shown that, during the estrous cycle of rats, fluctuating levels of estradiol mediate a change in the density of spine synapses in the hippocampus that is critically involved in memory and cognitive functions. Another brain area that plays a crucial role in cognition, especially in working memory, is the prefrontal cortex (PFC) (5). The function and structure of PFC neurons is also affected by gonadal steroids. Estrogens improve PFC-related cognitive performance of ovariectomized nonhuman primates (6) and rats (7). In line with this, changing levels of circulating estrogens influence the total number of spines in layer I of Walker's area 46 in young female rhesus monkeys (8). Similarly, Wallace et al. (7) have shown that ovariectomy decreases the dendritic spine density of layer II/III pyramidal cells in the medial PFC (mPFC) of female rats, suggesting that changes in spine synapses may mediate the effect of estrogens on PFC-relat...

Androgens Modulate Structure and Function of the Suprachiasmatic Nucleus Brain Clock

“…The postsynaptic marker PSD95 is a PDZ-domain protein associated with the PSD and is involved in the anchoring of numerous synaptic components, including NMDA and AMPA receptors and K ϩ channels (37). Gonadal steroids regulate dendritic spine density throughout development and in adulthood (12), with androgen-induced remodeling of neural circuits observed in the medial prefrontal cortex (38), hippocampus (39 -41), and the spinal nucleus of the bulbocavernosus (42). The present results indicate that the SCN is a novel locus of hormone-mediated structural plasticity in the brain.…”

Sex Hormones and Cognition: Neuroendocrine Influences on Memory and Learning

“…Instead, testosterone or nonaromatizable DHT ameliorated the reduced CA1 spine density in males (370). As in females, gonadectomy reduced medial prefrontal cortical spines in males, but estradiol benzoate had a more modest effect than DHT in ameliorating this reduction in the mPFC (235). The effects of androgens on hippocampal physiology and cognition in males are discussed in detail later.…”

“…Hajszan et al (235) reported that castrated wild type males displayed a decrease in the number of spine in the mPFC. However, systemic injections of 200 μL of DHT over 2 days reversed this decrease with the density of spines increasing by 136% and restoring the number to sham levels.…”

Estrogen Actions in the Brain and the Basis for Differential Action in Men and Women: A Case for Sex-Specific Medicines

“…Also as in the hippocampus, NMDA receptors play a significant role in this phenomenon, as evidenced by the ability of NMDA receptor antagonists to disrupt PFC-dependent cognition and reduce the number of asymmetric spine synapses (indicative of excitatory input) in the male PFC (Hajszan et al, 2008). However, unlike the hippocampus, estradiol can increase spine synapses in the castrated male rat PFC, albeit not as 186 potently as androgens (Hajszan et al, 2007). Estradiol also maintains dendritic spines in specific cortical regions of female nonhuman primates (Tang et al, 2004) and rats (Wallace et al, 2006), in parallel with positive effects on working memory; preliminary studies indicate that androgens may also positively affect spine synapses in the female PFC (Hajszan et al, 2008).…”