Estrogen increases the number of spinophilin‐immunoreactive spines in the hippocampus of young and aged female rhesus monkeys

Abstract

It is well documented that estrogen increases dendritic spine density in CA1 pyramidal cells of young female rats. However, this effect is attenuated in aged rats. We report here a quantitative analysis of estrogen effects on hippocampal spine number as visualized with antispinophilin in young (6-8 years old) and aged (19-23 years old) female rhesus monkeys, a species with a pattern of female endocrine senescence comparable to that of humans. Monkeys were ovariectomized and administered either vehicle or estradiol cypionate 3 months postovariectomy, followed by an additional dose 3 weeks later, with perfusion 24 hours after the last estrogen treatment. Immunolocalization of spinophilin, a spine-associated protein, was used for quantitative stereologic analyses of total spinophilin-immunoreactive spine numbers in CA1 stratum radiatum and the inner and outer molecular layers of dentate gyrus. In both young and aged female monkeys, the estrogen-treated groups had an increase in spinophilin-immunoreactive spines (37% in young, P <.005; 35% in aged, P <.05) compared with the untreated groups that amounted to more than 1 billion additional immunoreactive spines. The young group also showed a trend toward an estrogen-induced increase in immunoreactive spines in the dentate gyrus outer molecular layer, but this effect was not statistically significant (P =.097). We conclude that spine number in the rhesus monkey hippocampus is highly responsive to estrogen, yet, unlike the female rat, aged female rhesus monkeys retain the capacity for spine induction in response to estrogen. These data have important implications for cognitive effects of estrogen replacement in postmenopausal women and demonstrate that an estrogen replacement protocol that mimics normal physiological cycles with timed, intermittent peaks can have profound neurobiological effects.

Can endocrine disruptors influence neuroplasticity in the aging brain?

“…These observations have been confirmed and amplified in both primates and laboratory rodents (Leranth et al 2000;Leranth et al 2002;Hao et al 2003). Madeira et al (2001) correlated spine density with estrogen levels, which increase during the proestrus phase, and decrease during the diestrus phase.…”

“…Nonhuman primates, like humans, suffer declines in cognitive performance during advanced age, a decline correlated more closely with a decline in synaptic spine density than with actual cell loss. In aged female monkeys, which, like perimenopausal women have undergone endocrine senescence, estrogen treatment increased CA1 spine density (Leranth et al, 2002;Hao et al 2003). Moreover, in ovariectomized monkeys, both spine number and delayed-response performance were enhanced in response to estrogen treatment .…”

Stereologic estimates of total spinophilin-immunoreactive spine number in area 9 and the CA1 field: Relationship with the progression of Alzheimer's disease

“…Silver Enhancement was performed for 15-25 minutes at room temperature. After washing, the sections were mounted, dehydrated through ascending series of ethanol and xylene, and coverslipped with Biomount mounting medium (Electron Microscopy Sciences) [25,69]. This spinophilin antibody displays an excellent section penetration as confirmed by two previous stereologic studies using the same conditions [25,69] as well as by confocal microscopy.…”

“…Spinophilin immunoreactivity has been shown to be intense in the majority of dendritic spines of rat hippocampus [1]. It is present in about 93% of the dendritic spines in rhesus monkey hippocampus [25], but sparsely distributed in other portions of the dendrites, making it an excellent marker for quantitative assessment of spine numbers [25]. In order to explore the role of dendritic spine loss in cognitive decline, we performed a stereological analysis of spinophilin-immunoreactive puncta in the CA1 and CA3 fields of the hippocampus and area 9 in 12 elderly individuals prospectively assessed with the Mini Mental State Examination (MMSE) and Clinical Dementia Rating (CDR) scale.…”

Estrogen and brain-derived neurotrophic factor (BDNF) in hippocampus: Complexity of steroid hormone-growth factor interactions in the adult CNS

“…Thus, density, complexity and the number of spine synapses is increased by both estrogen and BDNF in hippocampus. It is noteworthy, however, that the exact nature of the changes in morphology may;e distinct: some studies indicate that spine shape or length change whereas other studies report that spine synapses are affected [41,[59][60][61][62][63][64][65][66][67][68][69][70][71]. Such data provide some caution to the assumption that estradiol and BDNF have exactly the same effects.…”