Aromatase inhibition abolishes LTP generation in female but not in male mice.
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.
Institute of Neuroanatomy, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
Ricardo
R
Vierk
Günter
G
Glassmeier
Lepu
L
Zhou
Nicola
N
Brandt
Lars
L
Fester
Danuta
D
Dudzinski
Wiebke
W
Wilkars
Roland A
RA
Bender
Martha
M
Lewerenz
Simon
S
Gloger
Lucas
L
Graser
Jürgen
J
Schwarz
Gabriele M
GM
Rune
D000818:Animals; D001141:Aromatase / Q000502:physiology*; D047072:Aromatase Inhibitors / Q000494:pharmacology*; D002478:Cells, Cultured; D051338:Cofilin 1 / Q000378:metabolism; D049229:Dendritic Spines / Q000187:drug effects / Q000648:ultrastructure; D004958:Estradiol / Q000097:blood; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D005260:Female; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D000077289:Letrozole; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009570:Nitriles / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012727:Sex Characteristics; D013569:Synapses / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure; D014230:Triazoles / Q000494:pharmacology*
D047072:Aromatase Inhibitors; D051338:Cofilin 1; D009570:Nitriles; D014230:Triazoles; D004958:Estradiol; D000077289:Letrozole; D001141:Aromatase