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.
"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). "
"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). "
[Show abstract][Hide abstract] 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
"More restricted actions can be had using agonists selective for the hormone's beta receptor which is, to a degree, concentrated in brain; such agonists are highly effective in LTP studies (Kramar et al., 2009). Evidence that estrogen is synthesized by hippocampal neurons and that hormone of local origin contributes significantly to hippocampal synaptic plasticity (Ooishi et al., 2012; Vierk et al., 2012) should also be noted here. Thus, it may be possible to find means to promote normal, likely activity-dependent, estrogen actions in a regionally restricted manner. "
[Show abstract][Hide abstract] ABSTRACT: The possibility of expanding memory or cognitive capabilities above the levels in high functioning individuals is a topic of intense discussion among scientists and in society at large. The majority of animal studies use behavioral endpoint measures; this has produced valuable information but limited predictability for human outcomes. Accordingly, several groups are pursuing a complementary strategy with treatments targeting synaptic events associated with memory encoding or forebrain network operations. Transcription and translation figure prominently in substrate work directed at enhancement. Notably, the question of why new proteins would be needed for a now-forming memory given that learning-driven synthesis presumably occurred throughout the immediate past has been largely ignored. Despite this conceptual problem, and some controversy, recent studies have reinvigorated the idea that selective gene manipulation is a plausible route to enhancement. Efforts to improve memory by facilitating synaptic encoding of information have also progressed, in part due of breakthroughs on mechanisms that stabilize learning-related, long-term potentiation (LTP). These advances point to a reductionistic hypothesis for a diversity of experimental results on enhancement, and identify under-explored possibilities. Cognitive enhancement remains an elusive goal, in part due to the difficulty of defining the target. The popular view of cognition as a collection of definable computations seems to miss the fluid, integrative process experienced by high functioning individuals. The neurobiological approach obviates these psychological issues to directly test the consequences of improving throughput in networks underlying higher order behaviors. The few relevant studies testing drugs that selectively promote excitatory transmission indicate that it is possible to expand cortical networks engaged by complex tasks and that this is accompanied by capabilities not found in normal animals.
Frontiers in Systems Neuroscience 05/2014; 8:90. DOI:10.3389/fnsys.2014.00090
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