Aromatase Inhibition Abolishes LTP Generation in Female But Not in Male Mice

Institute of Neuroanatomy, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 06/2012; 32(24):8116-26. DOI: 10.1523/JNEUROSCI.5319-11.2012
Source: PubMed


Inhibitors of aromatase, the final enzyme of estradiol synthesis, are suspected of inducing memory deficits in women. In previous experiments, we found hippocampal spine synapse loss in female mice that had been treated with letrozole, a potent aromatase inhibitor. In this study, we therefore focused on the effects of letrozole on long-term potentiation (LTP), which is an electrophysiological parameter of memory and is known to induce spines, and on phosphorylation of cofilin, which stabilizes the spine cytoskeleton and is required for LTP in mice. In acute slices of letrozole-treated female mice with reduced estradiol serum concentrations, impairment of LTP started as early as after 6 h of treatment and progressed further, together with dephosphorylation of cofilin in the same slices. Theta-burst stimulation failed to induce LTP after 1 week of treatment. Impairment of LTP was followed by spine and spine synapse loss. The effects were confirmed in vitro by using hippocampal slice cultures of female mice. The sequence of effects in response to letrozole were similar in ovariectomized female and male mice, with, however, differences as to the degree of downregulation. Our data strongly suggest that impairment of LTP, followed by loss of mushroom spines and spine synapses in females, may have implications for memory deficits in women treated with letrozole.

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    • "The interpretation of the observed MRI signal difference in terms of the underlying cellular substrate may be guided by the literature on rodents. We have previously shown that estradiol affects hippocampal spine density in female, but not in male, rodents (Vierk et al., 2012; Zhou et al., 2014). Others describe a similar sexual dimorphic effect of estradiol only in females on fiber outgrowth and sprouting responses (Barker and Galea, 2008; Leranth et al., 2003; Morse et al., 1986; Spritzer and Galea, 2007; Woolley and McEwen, 1993). "
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    ABSTRACT: In estrogen-induced synaptic plasticity, a correlation of structure, function and behavior in the hippocampus has been widely established. 17ß-estradiol has been shown to increase dendritic spine density on hippocampal neurons and is accompanied by enhanced long-term potentiation and improved performance of animals in hippocampus-dependent memory tests. After inhibition of aromatase, the final enzyme of estradiol synthesis, with letrozole we consistently found a strong and significant impairment of long-term potentiation (LTP) in female mice as early as after six hours of treatment. LTP impairment was followed by loss of hippocampal spine synapses in the hippocampal CA1 area. Interestingly, these effects were not found in male animals. In the Morris water maze test, chronic administration of letrozole did not alter spatial learning and memory in either female or in male mice. In humans, analogous effects of estradiol on hippocampal morphology and physiology were observed using neuroimaging techniques. However, similar to our findings in mice, an effect of estradiol on memory performance has not been consistently identified/observed. Copyright © 2015. Published by Elsevier Inc.
    Hormones and Behavior 05/2015; 74. DOI:10.1016/j.yhbeh.2015.05.008 · 4.63 Impact Factor
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    • "Further, systemic injections of letrozole have been associated with impaired LTP and transient dephosphorylation of the actin binding protein cofilin in gonadally-intact male rats and both intact and ovariectomized female rats (Vierk et al., 2012). Letrozole also reduced the numbers of mature spines, thin spines, and spine synapses in females, but only decreased thin spines in males (Vierk et al., 2012), suggesting a potential sex difference in the role of local E 2 in regulating hippocampal spinogenesis. Clues to the behavioral significance of de novo hippocampal E 2 synthesis come from studies of zebra finches, which report that E 2 is rapidly synthesized in the auditory caudo-medial nidopallium (NCM) of males during behavioral experiences such as exposure to female conspecifics or conspecific song (Remage-Healey et al., 2008). "
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    ABSTRACT: Since the publication of the 1998 special issue of Hormones and Behavior on estrogens and cognition, substantial progress has been made towards understanding the molecular mechanisms through which 17β-estradiol (E2) regulates hippocampal plasticity and memory. Recent research has demonstrated that rapid effects of E2 on hippocampal cell signaling, epigenetic processes, and local protein synthesis are necessary for E2 to facilitate the consolidation of object recognition and spatial memories in ovariectomized female rodents. These effects appear to be mediated by non-classical actions of the intracellular estrogen receptors ERα and ERβ, and possibly by membrane-bound ERs such as the G-protein-coupled estrogen receptor (GPER). New findings also suggest a key role of hippocampally-synthesized E2 in regulating hippocampal memory formation. The present review discusses these findings in detail and suggests avenues for future study. Copyright © 2015. Published by Elsevier Inc.
    Hormones and Behavior 05/2015; 74. DOI:10.1016/j.yhbeh.2015.05.001 · 4.63 Impact Factor
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    • "In rodents, inhibition of hippocampal E 2 synthesis by the aromatase inhibitor letrozole significantly decreases hippocampal synapse number and synaptic spine density in vitro (Kretz et al., 2004), indicating an important role for local E 2 synthesis in hippocampal synaptic morphology. However, letrozole impairs hippocampal LTP in female, but not male, mice (Vierk et al., 2012), suggesting a sex difference in the role of locally synthesized E 2 in hippocampal plasticity. Such sex differences could contribute to the premature hippocampal memory decline observed in reproductively senescent female rodents relative to males (Markowska, 1999; Frick et al., 2000). "
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    ABSTRACT: Hippocampal memory formation is highly regulated by post-translational histone modifications and DNA methylation. Accordingly, these epigenetic processes play a major role in the effects of modulatory factors, such as sex steroid hormones, on hippocampal memory. Our laboratory recently demonstrated that the ability of the potent estrogen 17β-estradiol (E2) to enhance hippocampal-dependent novel object recognition memory in ovariectomized female mice requires ERK-dependent histone H3 acetylation and DNA methylation in the dorsal hippocampus. Although these data provide valuable insight into the chromatin modifications that mediate the memory-enhancing effects of E2, epigenetic regulation of gene expression is enormously complex. Therefore, more research is needed to fully understand how E2 and other hormones employ epigenetic alterations to shape behavior. This review discusses the epigenetic alterations shown thus far to regulate hippocampal memory, briefly reviews the effects of E2 on hippocampal function, and describes in detail our work on epigenetic regulation of estrogenic memory enhancement.
    Frontiers in Neuroendocrinology 05/2014; 35(4). DOI:10.1016/j.yfrne.2014.05.001 · 7.04 Impact Factor
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