Letrozole induces worse hippocampal synaptic and dendritic changes and spatial memory impairment than ovariectomy in adult female mice

Liu, Mengying; Xing, Fang-Zhou; Bian, Chen; Zhao, Yangang; Zhao, Jingming; Liu, Yan; Zhang, Jiqiang

doi:10.1016/j.neulet.2019.05.006

Cited by 15 publications

(5 citation statements)

References 44 publications

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“…Impairment induced by the letrozole dose of 0.1 mg/kg is in agreement with previously reported impairment of water maze reference memory learning caused by similar dose, 0.16 mg/kg, injected intraperitoneally (i.p.) in female C57Bl mice (Liu et al, 2019). Similarly to an effect in female mice, i.p.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast to intrahippocampal injections, systemic administration of letrozole that is clinically relevant shows inconsistent effect on spatial learning and memory in mice and rats, ranging from impairment (Zameer and Vohora, 2017, Liu et al, 2019) or no effect (Meng et al, 2011;(Vierk et al, 2015) in mice, to improvement in rats (Alejandre-Gomez et al, 2007, Aydin et al, 2008). In addition to differences in the response to letrozole in rats and mice, there are differences among mouse strains (Cestari et al, 1999; Ciamei et al, 2000; Lipartiti et al, 1993) that can affect the effects of letrozole on cognitive performance.…”

Section: Introductionmentioning

confidence: 99%

“…Therefore, comparison of different mouse strains provides valuable information about the importance of genetic background in behavioral and pharmacodynamic phenotypes (Jacobson and Cryan, 2005). To date, C57Bl mice were the most often used strain in studies evaluating effect of letrozle on spatial learning (Meng et al, 2011; Liu et al, 2019; Vierk et al, 2015). Since our goal was to evaluate the effect of prolonged exposure to letrozole on cognitive functions in an animal model used in breast cancer research (Orlandella et al, 2021), the present study used female BALB/c mice.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Letrozole delays acquisition of water maze task in female BALB/c mice: possible involvement of anxiety

Mamczarz

Lane

Merchenthaler

2022

Preprint

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Letrozole, an aromatase inhibitor (AI), is used as an adjuvant therapy in estrogen receptor-positive (ER+) breast cancer patients. Similar to other AIs, it induces many side effects, including impaired cognition. Despite its negative effect in humans, results from animal models are inconsistent and suggest that letrozole can either impair or improve cognition. Here we studied effects of letrozole on cognitive behavior of adult female BALB/c mice, a relevant animal model for breast cancer studies. Mice were continuously treated with once-a-day subcutaneous (s.c.) injections of letrozole (0.1 or 0.3 mg/kg/day) or vehicle and subjected to behavioral testing starting on day 21 after treatment initiation. During the treatments, vaginal smears were taken from the mice to evaluate estrous cyclicity. Both doses of letrozole suspended cyclicity and the smears showed that the mice were in constant metestrus. Exposure to letrozole did not significantly affect response to novelty measured as a locomotor activity in open field. However, repeated testing in open field (4 days x 15 min) revealed that letrozole 0.3 mg/kg facilitated locomotor habituation (a form of non-associative learning), significantly reducing locomotor activity on 3rd and 4th day of testing. These findings suggest that certain doses of letrozole may have positive effects on cognitive behavior. Training to find a hidden platform in the Morris water maze (15 days x 4 trials), however, indicated that letrozole 0.1 mg/kg-treated mice had significant learning impairment, as, throughout the training, they swam longer times than vehicle-treated mice to reach the hidden platform. Similarly, in a probe test performed 72 h after the last day of the training, letrozole 0.1 mg/kg-treated mice did not show preference for the training platform zones. These results indicate that cognitive impairments reported by women treated with letrozole can be captured in BALB/c mice treated with clinically relevant doses of the drug. Interestingly, most of the letrozole 0.1 mg/kg-treated mice were able to learn the new platform position in reversal training and performed similar to control mice in a reversal probe test. Results of the reversal test suggest that letrozole did not completely disrupt spatial navigation but rather delayed acquisition of spatial information. The current study shows that letrozole dose dependently modulates behavioral response and that its effects are task dependent.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Letrozole delays acquisition of water maze task in female BALB/c mice: possible involvement of anxiety

Mamczarz

Lane

Merchenthaler

2022

Preprint

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“…Several mechanisms have been implicated to underlie NDE 2 regulation of synaptic plasticity and memory, including (1) regulation of actin cytoskeleton polymerization/depolymerization and PSD proteins, (2) enhancement of rapid MAPK/ERK and PI3K-AKT signaling, (3) regulation of CREB-BDNF signaling, and (4) mediation by estrogen receptors and the steroid nuclear receptor co-activator, SRC-1. In support of NDE 2 regulation of actin polymerization/depolymerization, which is critical for spine formation, several studies found that letrozole treatment in mice resulted in disruption of actin cytoskeleton polymerization dynamics, which was associated with loss of hippocampal spine formation [75,77,97]. Letrozole was also shown to downregulate the actin remodeling proteins profilin-1, phospho-cofilin, and rictor in the mouse hippocampus and in mHippoE-14 hippocampal cells in vitro [75], indicating that NDE 2 regulates actin polymerization dynamics through regulating expression and/or activity of these key actin remodeling proteins.…”

Section: Mechanisms Underlying Nde 2 Effects On Synaptic Plasticity and Memorymentioning

confidence: 98%

Neuron-Derived Estrogen—A Key Neuromodulator in Synaptic Function and Memory

Brann

Wang

et al. 2021

IJMS

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In addition to being a steroid hormone, 17b-estradiol (E2) is also a neurosteroid produced in neurons in various regions of the brain of many species, including humans. Neuron-derived E2 (NDE2) is synthesized from androgen precursors via the action of the biosynthetic enzyme aromatase, which is located at synapses and in presynaptic terminals in neurons in both the male and female brain. In this review, we discuss evidence supporting a key role for NDE2 as a neuromodulator that regulates synaptic plasticity and memory. Evidence supporting an important neuromodulatory role of NDE2 in the brain has come from studies using aromatase inhibitors, aromatase overexpression in neurons, global aromatase knockout mice, and the recent development of conditional forebrain neuron-specific knockout mice. Collectively, these studies demonstrate a key role of NDE2 in the regulation of synapse and spine density, efficacy of excitatory synaptic transmission and long-term potentiation, and regulation of hippocampal-dependent recognition memory, spatial reference memory, and contextual fear memory. NDE2 is suggested to achieve these effects through estrogen receptor-mediated regulation of rapid kinase signaling and CREB-BDNF signaling pathways, which regulate actin remodeling, as well as transcription, translation, and transport of synaptic proteins critical for synaptic plasticity and function.

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“… 40 On the other hand, it seem that brain E2, which derived from de novo synthesis from aromatase (estrogen synthase) by catalyzing androgens, 49 showed positive regulation on brain SRC-1 as evidenced by results from aromatase inhibitors. 54 , 55 , 56 , 57 However, it must be pointed out that the above evidences were indeed indirect, since letrozole functions to inhibit not only central but also peripheral E2 synthesis. Therefore, how brain E2 regulated the expression of SRC-1 needs further experiments.…”

Section: Steroidal Regulation Of Brain Src-1mentioning

confidence: 99%

Steroid receptor coactivator-1: The central intermediator linking multiple signals and functions in the brain and spinal cord

Meng¹,

Wang²,

Zhang³

et al. 2022

Genes & Diseases

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Letrozole induces worse hippocampal synaptic and dendritic changes and spatial memory impairment than ovariectomy in adult female mice

Cited by 15 publications

References 44 publications

Letrozole delays acquisition of water maze task in female BALB/c mice: possible involvement of anxiety

Letrozole delays acquisition of water maze task in female BALB/c mice: possible involvement of anxiety

Neuron-Derived Estrogen—A Key Neuromodulator in Synaptic Function and Memory

Steroid receptor coactivator-1: The central intermediator linking multiple signals and functions in the brain and spinal cord

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