TY - JOUR
T1 - Aromatase inhibitors induce spine synapse loss in the hippocampus of ovariectomized mice
AU - Zhou, Lepu
AU - Fester, Lars
AU - Von Blittersdorff, Breda
AU - Hassu, Basel
AU - Nogens, Henning
AU - Prange-Kiel, Janine
AU - Jarry, Hubertus
AU - Wegscheider, Karl
AU - Rune, Gabriele M.
N1 - Copyright:
Copyright 2010 Elsevier B.V., All rights reserved.
PY - 2010/3
Y1 - 2010/3
N2 - Recently, inhibition of estrogen synthesis by aromatase inhibitors has become a favored therapy for breast cancer in postmenopausal women. Estrogen is, however, important for synapse formation in the hippocampus. Inhibition of aromatase induces spine synapse loss in organotypic hippocampal slice cultures. We therefore studied the effect of systemic treatment with the potent aromatase inhibitor letrozole on spine synapse formation and synaptic proteins in the hippocampi of female mice for periods of 7 d and 4 wk. In cyclic, letrozole-treated females and in ovariectomized, letrozole-treated females, the number of spine synapses was significantly reduced in the hippocampus but not in the prefrontal or cerebellar cortex. Consequently, the expression of the N-methyl-D-aspartate receptor NR1 was significantly down-regulated after treatment with letrozole. In cyclic animals the expression of the synaptic proteins synaptophysin and spinophilin was down-regulated in response to letrozole. In ovariectomized animals, however, protein expression was down-regulated after 7 d of treatment, whereas the expression was up-regulated after 4 wk of treatment. Our results indicate that systemic inhibition of aromatase in mice affects structural synaptic plasticity in the hippocampus. This may contribute to cognitive deficits in postmenopausal women treated with aromatase inhibitors.
AB - Recently, inhibition of estrogen synthesis by aromatase inhibitors has become a favored therapy for breast cancer in postmenopausal women. Estrogen is, however, important for synapse formation in the hippocampus. Inhibition of aromatase induces spine synapse loss in organotypic hippocampal slice cultures. We therefore studied the effect of systemic treatment with the potent aromatase inhibitor letrozole on spine synapse formation and synaptic proteins in the hippocampi of female mice for periods of 7 d and 4 wk. In cyclic, letrozole-treated females and in ovariectomized, letrozole-treated females, the number of spine synapses was significantly reduced in the hippocampus but not in the prefrontal or cerebellar cortex. Consequently, the expression of the N-methyl-D-aspartate receptor NR1 was significantly down-regulated after treatment with letrozole. In cyclic animals the expression of the synaptic proteins synaptophysin and spinophilin was down-regulated in response to letrozole. In ovariectomized animals, however, protein expression was down-regulated after 7 d of treatment, whereas the expression was up-regulated after 4 wk of treatment. Our results indicate that systemic inhibition of aromatase in mice affects structural synaptic plasticity in the hippocampus. This may contribute to cognitive deficits in postmenopausal women treated with aromatase inhibitors.
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U2 - 10.1210/en.2009-0254
DO - 10.1210/en.2009-0254
M3 - Article
C2 - 20097718
AN - SCOPUS:77149155316
SN - 0013-7227
VL - 151
SP - 1153
EP - 1160
JO - Endocrinology
JF - Endocrinology
IS - 3
ER -