The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
J Neurosci. 2019 Jun 19;39(25):4874-4888. doi: 10.1523/JNEUROSCI.2772-18.2019. Epub 2019 Apr 16.
Surgical ovariectomy has been shown to reduce spine density in hippocampal CA1 pyramidal cells of rodents, and this reduction is reversed by 17β-estradiol (E2) treatment in a model of human estrogen replacement therapy. Here, we report reduction of spine density in apical dendrites of layer 5 pyramidal neurons of several neocortical regions that is reversed by subsequent E2 treatment in ovariectomized (OVX) female Thy1M-EGFP mice. We also found that OVX-associated reduction of spine density in somatosensory cortex was accompanied by a reduction in miniature EPSC (mEPSC) frequency (but not mIPSC frequency), indicating a change in functional synapses. OVX-associated spine loss in somatosensory cortex was also rescued by an agonist of the G-protein-linked estrogen receptor (GPER) but not by agonists of the classic estrogen receptors ERα/ERβ, whereas the opposite selectivity was found in area CA1. Acute treatment of neocortical slices with E2 also rescued the OVX-associated reduction in mEPSC frequency, which could be mimicked by a GPER agonist and abolished by a GPER antagonist. Time-lapse two-photon imaging showed that OVX-associated reduction in spine density is achieved by both an increase in spine loss rate and a decrease in spine gain rate and that subsequent rescue by E2 reversed both of these processes. Crucially, the spines added after E2 rescue were no more likely to reappear at or nearby the sites of pre-OVX spines than those in control mice treated with vehicle. Thus, a model of estrogen replacement therapy, although restoring spine density and dynamics, does not entirely restore functional connectivity. Estrogen replacement therapy following menopause or surgical removal of the ovaries is a widespread medical practice, yet little is known about the consequences of such treatment for cells in the brain. Here, we show that estrogen replacement reverses some of the effects of surgical removal of the ovaries on the structure and function of brain cells in the mouse. Yet, importantly, the fine wiring of the brain is not returned to the presurgery state by estrogen treatment, suggesting lasting functional consequences.
手术切除卵巢已被证明会减少啮齿动物海马 CA1 锥体神经元的脊柱密度，而这种减少在人类雌激素替代疗法的模型中可以通过 17β-雌二醇（E2）治疗逆转。在这里，我们报告了在切除卵巢的 Thy1M-EGFP 雌鼠中，几种新皮层区域的 5 层锥体神经元的树突棘密度减少，随后的 E2 治疗可以逆转这种减少。我们还发现，与卵巢切除相关的躯体感觉皮层的树突棘密度减少伴随着小细胞外突触及频率（但不是 mIPSC 频率）的降低，表明功能性突触发生了变化。躯体感觉皮层与卵巢切除相关的树突棘丢失也被 G 蛋白偶联雌激素受体（GPER）激动剂挽救，但不是经典雌激素受体 ERα/ERβ 的激动剂，而在 CA1 区则发现了相反的选择性。急性给予新皮层切片 E2 也挽救了与卵巢切除相关的 mEPSC 频率降低，这可以被 GPER 激动剂模拟，而被 GPER 拮抗剂消除。双光子延时成像显示，与卵巢切除相关的树突棘密度降低是通过增加树突棘丢失率和降低树突棘获得率来实现的，而随后的 E2 挽救逆转了这两个过程。至关重要的是，E2 挽救后添加的树突棘再次出现在与预卵巢切除的树突棘相同或附近的位置的可能性并不比用载体处理的对照组小鼠中添加的树突棘更高。因此，尽管雌激素替代疗法恢复了脊柱密度和动态，但并没有完全恢复功能连接。绝经后或手术切除卵巢后的雌激素替代疗法是一种广泛的医疗实践，但对这种治疗对大脑细胞的影响知之甚少。在这里，我们表明，雌激素替代疗法可以逆转手术切除卵巢对小鼠脑细胞结构和功能的一些影响。然而，重要的是，大脑的精细布线并没有通过雌激素治疗恢复到术前状态，这表明存在持久的功能后果。
