Estradiol Increases Dendritic Spine Density by Reducing GABA Neurotransmission in Hippocampal Neurons
Estradiol Increases Dendritic Spine Density by Reducing GABA Neurotransmission in Hippocampal Neurons
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DOI：
10.1523/jneurosci.18-07-02550.1998
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发表时间：
1998-04
期刊：
影响因子：
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通讯作者：
D. Murphy;N. Cole;V. Greenberger;M. Segal
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文献类型：
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作者：
D. Murphy;N. Cole;V. Greenberger;M. Segal
我们先前已经证明，雌二醇导致培养的大鼠海马神经元树突棘密度增加两倍，就像在体内一样。最近，雌激素受体已被定位到棘抑制海马中间神经元，表明其对棘锥体神经元的影响可能是间接的。因此，我们研究了雌二醇通过调节抑制培养的海马中间神经元来影响棘密度的可能性。免疫细胞化学，雌激素受体被发现与谷氨酸脱羧酶（GAD）阳性神经元（约21%的总神经元的文化）共定位。暴露于雌二醇1天的文化造成了显着减少（高达80%）的GAD含量的interneurons，通过免疫组化和Western印迹法测定。此外，在培养物中的GAD阳性神经元的数量减少到总细胞群的12%。此外，GABA能微型IPSC的大小和频率减少雌二醇，而微型EPSC的频率增加。然后，我们模仿建议的影响，雌二醇阻断GABA的合成与巯基丙酸（MA）。用MA处理的培养物表达了剂量依赖性的GABA免疫染色减少，这与雌二醇相似。MA处理的文化表现出显着的树突棘密度增加50%，比对照组，类似于雌二醇产生的。这些结果表明，雌二醇降低海马中的GABA能抑制，这似乎有效地增加了对锥体细胞的兴奋性驱动，因此可能提供了形成新的树突棘的机制。
We have previously shown that estradiol causes a twofold rise in dendritic spine density in cultured rat hippocampal neurons, as it doesin vivo. More recently, estrogen receptors have been localized to aspiny inhibitory hippocampal interneurons, indicating that their effect on spiny pyramidal neurons may be indirect. We therefore examined the possibility that estradiol affects spine density by regulating inhibition in cultured hippocampal interneurons. Immunocytochemically, estrogen receptors were found to be co-localized with glutamate decarboxylase (GAD)-positive neurons (∼21% of total neurons in the culture). Exposure of cultures to estradiol for 1 d caused a marked decrease (up to 80%) in the GAD content of the interneurons, measured both by immunohistochemistry and Western blotting. Also, the number of GAD-positive neurons in the cultures decreased to 12% of the total cell population. Moreover, GABAergic miniature IPSCs were reduced in both size and frequency by estradiol, whereas miniature EPSCs increased in frequency. We then mimicked the proposed effects of estradiol by blocking GABA synthesis with mercaptopropionic acid (MA). Cultures treated with MA expressed a dose-dependent decrease in GABA immunostaining that mimicked that seen with estradiol. MA-treated cultures displayed a significant 50% increase in dendritic spine density over controls, similar to that produced by estradiol. These results indicate that estradiol decreases GABAergic inhibition in the hippocampus, which appears to effectively increase the excitatory drive on pyramidal cells, and thus may provide a mechanism for formation of new dendritic spines.