Institute of Neuroanatomy, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
J Neurosci. 2012 Jun 13;32(24):8116-26. doi: 10.1523/JNEUROSCI.5319-11.2012.
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.
芳香酶抑制剂是雌二醇合成的最后一种酶，被怀疑会导致女性记忆力减退。在之前的实验中，我们发现用来曲唑（一种强效的芳香酶抑制剂）处理的雌性小鼠海马锥体突触丢失。因此，在这项研究中，我们专注于来曲唑对长时程增强（LTP）的影响，LTP 是记忆的一种电生理参数，已知它可以诱导产生棘突，以及对丝切蛋白磷酸化的影响，丝切蛋白稳定棘突细胞骨架，是小鼠 LTP 所必需的。在血清雌二醇浓度降低的经来曲唑处理的雌性小鼠的急性切片中，早在治疗后 6 小时就开始出现 LTP 损伤，并进一步进展，同时同一切片中的丝切蛋白去磷酸化。经过 1 周的治疗，θ爆发刺激未能诱导 LTP。LTP 的损伤伴随着棘突和棘突突触的丢失。体外实验也证实了这些影响，使用了雌性小鼠的海马切片培养物。对来曲唑的反应的一系列影响在去卵巢的雌性和雄性小鼠中相似，但下调的程度不同。我们的数据强烈表明，LTP 的损伤，随后是雌性小鼠蘑菇状棘突和棘突突触的丢失，可能与接受来曲唑治疗的女性的记忆力减退有关。
