Androgen Effects on Hippocampal CA1 Spine Synapse Numbers Are Retained in Tfm Male Rats with Defective Androgen Receptors

MacLusky, Neil J.; Hajszán, Tibor; Johansen, Jamie A.; Jordan, Cynthia L.; Leranth, Csaba

doi:10.1210/en.2005-0673

Cited by 57 publications

(50 citation statements)

References 42 publications

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“…Previous studies have also shown that these doses of DHT and EB are sufficient to reproduce the density of hippocampal spine synapses observed in proestrous females (4) or in intact males (15). Thus, the hippocampi of these animals were also processed and the number of CA1 spine synapses was determined as published previously (16), which served as evidence of appropriate hormonal influence on the brain. Two additional groups of animals were left gonadally intact and untreated to serve as positive controls.…”

Section: Methodsmentioning

confidence: 95%

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

et al. 2007

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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...

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Section: Methodsmentioning

confidence: 95%

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

et al. 2007

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“…The number of spine synapses in the CA1sr, CA3sl/sr, DGsm, and layer II/III of Walker's area 46 (PFC) was calculated as described in ref. 62. Serial sections (200 m) were cut in the coronal plane throughout the entire PFC and the hippocampus on a vibratome, and then systematically sorted into 10 groups.…”

Section: Methodsmentioning

confidence: 99%

“…The boundaries of Walker's area 46 were determined according to the method described by Tang et al (49). Subsequently, 20 sampling sites for electron microscopic analysis were localized in each sampling area using a systematic-random approach, as modified from MacLusky et al (62). In brief, we used a two-dimensional coordinate system with length (L) and height (H) axes.…”

Section: Methodsmentioning

confidence: 99%

Bisphenol A prevents the synaptogenic response to estradiol in hippocampus and prefrontal cortex of ovariectomized nonhuman primates

Leranth

Hajszán²,

Szigeti‐Buck

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Exposure measurements from several countries indicate that humans are routinely exposed to low levels of bisphenol A (BPA), a synthetic xenoestrogen widely used in the production of polycarbonate plastics. There is considerable debate about whether this exposure represents an environmental risk, based on reports that BPA interferes with the development of many organs and that it may alter cognitive functions and mood. Consistent with these reports, we have previously demonstrated that BPA antagonizes spine synapse formation induced by estrogens and testosterone in limbic brain areas of gonadectomized female and male rats. An important limitation of these studies, however, is that they were based on rodent animal models, which may not be representative of the effects of human BPA exposure. To address this issue, we examined the influence of continuous BPA administration, at a daily dose equal to the current U.S. Environmental Protection Agency's reference safe daily limit, on estradiol-induced spine synapse formation in the hippocampus and prefrontal cortex of a nonhuman primate model. Our data indicate that even at this relatively low exposure level, BPA completely abolishes the synaptogenic response to estradiol. Because remodeling of spine synapses may play a critical role in cognition and mood, the ability of BPA to interfere with spine synapse formation has profound implications. This study is the first to demonstrate an adverse effect of BPA on the brain in a nonhuman primate model and further amplifies concerns about the widespread use of BPA in medical equipment, and in food preparation and storage. monkey ͉ stereology ͉ synaptic plasticity S ince the 1950s, the synthetic xenoestrogen bisphenol A (BPA) has been used in the manufacture of plastics with a broad range of uses, including dental prostheses and sealants (1), the polycarbonate lining of metal cans used to preserve foods (2), baby bottles (3) and the clear plastic cages used to house laboratory animals (4). BPA also is used as an additive in many products. Its global production rate is Ͼ6 billion pounds per year. Polycarbonate is less durable than commonly believed, because the ester bond linking BPA molecules to the plastic can be hydrolyzed. With the rate of hydrolysis increasing dramatically under both acidic and basic conditions, and at elevated temperatures, BPA leaches out of polycarbonate containers into food and beverages under normal conditions of use (3-5). As a result, exposure measurement data from several countries, including the United States, indicate that humans are widely exposed to low levels of BPA on a continuous basis (6).There is considerable debate about whether this exposure represents an environmental risk, based mostly on the fact that some hormonally active chemicals exhibit radically different potencies in different bioassay systems, making it difficult to assess their potential adverse effects (7). For example, in a two-generation trial in rats, BPA was reported to not induce significant reproductive abnormalities at ...

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“…This hypothesis would account for our observations of dual agonist/antagonist actions of antiandrogens in neuroprotection and match our findings of a rapid, non-genomic neuroprotective pathway specific to apoptotic insults. Another example is the finding that flutamide mimicked rather than inhibited DHT-induced increases in hippocampal spine density (MacLusky et al, 2004), an androgen action found to be independent of classic AR-dependent genomic mechanisms (MacLusky et al, 2006). However, antiandrogens are not predicted to be AR agonists for all non-genomic signaling pathways and thus findings that antiandrogens block androgen protection and or fail to mimic androgen protection are expected.…”

Section: Antiandrogens and Ar-dependent Neuroprotectionmentioning

confidence: 99%

Androgen cell signaling pathways involved in neuroprotective actions

Pike

Nguyen

Ramsden

et al. 2008

Hormones and Behavior

110

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As a normal consequence of aging in men, testosterone levels significantly decline in both serum and brain. Age-related testosterone depletion results in increased risk of dysfunction and disease in androgen-responsive tissues, including brain. Recent evidence indicates that one deleterious effect of age-related testosterone loss in men is increased risk for Alzheimer's disease (AD). We discuss recent findings from our laboratory and others that identify androgen actions implicated in protecting the brain against neurodegenerative diseases and begin to define androgen cell signaling pathways that underlie these protective effects. Specifically, we focus on the roles of androgens as (1) endogenous negative regulators of β-amyloid accumulation, a key event in AD pathogenesis, and (2) neuroprotective factors that utilize rapid non-genomic signaling to inhibit neuronal apoptosis. Continued elucidation of cell signaling pathways that contribute to protective actions of androgens should facilitate the development of targeted therapeutic strategies to combat AD and other agerelated neurodegenerative diseases.

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Androgen Effects on Hippocampal CA1 Spine Synapse Numbers Are Retained in Tfm Male Rats with Defective Androgen Receptors

Cited by 57 publications

References 42 publications

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

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

Bisphenol A prevents the synaptogenic response to estradiol in hippocampus and prefrontal cortex of ovariectomized nonhuman primates

Androgen cell signaling pathways involved in neuroprotective actions

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