Aromatase inhibition abolishes LTP generation in female but not in male mice.
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Aromatase inhibition abolishes LTP generation in female but not in male mice. / Vierk, Ricardo; Glassmeier, Günter; Zhou, Lepu; Brandt, Nicola; Fester, Lars; Dudzinski, Danuta; Wilkars, Wiebke; Bender, Roland; Lewerenz, Martha; Gloger, Simon; Graser, Lucas; Schwarz, Jürgen; Rune, Gabriele M.
In: J NEUROSCI, Vol. 32, No. 24, 24, 2012, p. 8116-8126.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Aromatase inhibition abolishes LTP generation in female but not in male mice.
AU - Vierk, Ricardo
AU - Glassmeier, Günter
AU - Zhou, Lepu
AU - Brandt, Nicola
AU - Fester, Lars
AU - Dudzinski, Danuta
AU - Wilkars, Wiebke
AU - Bender, Roland
AU - Lewerenz, Martha
AU - Gloger, Simon
AU - Graser, Lucas
AU - Schwarz, Jürgen
AU - Rune, Gabriele M.
PY - 2012
Y1 - 2012
N2 - 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.
AB - 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.
KW - Animals
KW - Male
KW - Female
KW - Cells, Cultured
KW - Mice
KW - Mice, Inbred C57BL
KW - Rats
KW - Rats, Wistar
KW - Estradiol/blood
KW - Aromatase/physiology
KW - Aromatase Inhibitors/pharmacology
KW - Cofilin 1/metabolism
KW - Dendritic Spines/drug effects/ultrastructure
KW - Excitatory Postsynaptic Potentials/drug effects/physiology
KW - Hippocampus/cytology/drug effects/physiology
KW - Long-Term Potentiation/drug effects/physiology
KW - Nitriles/pharmacology
KW - Sex Characteristics
KW - Synapses/drug effects/physiology/ultrastructure
KW - Triazoles/pharmacology
KW - Animals
KW - Male
KW - Female
KW - Cells, Cultured
KW - Mice
KW - Mice, Inbred C57BL
KW - Rats
KW - Rats, Wistar
KW - Estradiol/blood
KW - Aromatase/physiology
KW - Aromatase Inhibitors/pharmacology
KW - Cofilin 1/metabolism
KW - Dendritic Spines/drug effects/ultrastructure
KW - Excitatory Postsynaptic Potentials/drug effects/physiology
KW - Hippocampus/cytology/drug effects/physiology
KW - Long-Term Potentiation/drug effects/physiology
KW - Nitriles/pharmacology
KW - Sex Characteristics
KW - Synapses/drug effects/physiology/ultrastructure
KW - Triazoles/pharmacology
M3 - SCORING: Journal article
VL - 32
SP - 8116
EP - 8126
JO - J NEUROSCI
JF - J NEUROSCI
SN - 0270-6474
IS - 24
M1 - 24
ER -