Aromatase inhibitors induce spine synapse loss in the hippocampus of ovariectomized mice.
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.
Zhou
Lepu
L
Institute of Anatomy I, Cellular Neurobiology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.
Fester
Lars
L
von Blittersdorff
Breda
B
Hassu
Basel
B
Nogens
Henning
H
Prange-Kiel
Janine
J
Jarry
Hubertus
H
Wegscheider
Karl
K
Rune
Gabriele M
GM
D000818:Animals; D047072:Aromatase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects*; D015536:Down-Regulation; D030762:Estrous Cycle; D005260:Female; D006624:Hippocampus / Q000187:drug effects* / Q000648:ultrastructure; D000077289:Letrozole; D051379:Mice; D008810:Mice, Inbred C57BL; D008840:Microfilament Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009570:Nitriles / Q000008:administration & dosage / Q000009:adverse effects*; D010052:Ovariectomy; D013569:Synapses / Q000187:drug effects*; D016708:Synaptophysin / Q000378:metabolism; D014230:Triazoles / Q000008:administration & dosage / Q000009:adverse effects*; D000099273:Neurabins
D047072:Aromatase Inhibitors; D000077289:Letrozole; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; D009570:Nitriles; D016708:Synaptophysin; D014230:Triazoles; D000099273:Neurabins