Viral vector-mediated overexpression of estrogen receptor-alpha in striatum enhances the estradiol-induced motor activity in female rats and estradiol-modulated GABA release.
Viral vector-mediated overexpression of estrogen receptor-alpha in striatum enhances the estradiol-induced motor activity in female rats and estradiol-modulated GABA release.
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DOI：
10.1523/jneurosci.4647-08.2009
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发表时间：
2009-02-11
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影响因子：
--
通讯作者：
Becker JB
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文献类型：
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作者：
Schultz KN;von Esenwein SA;Hu M;Bennett AL;Kennedy RT;Musatov S;Toran-Allerand CD;Kaplitt MG;Young LJ;Becker JB
经典的雌激素受体信号传导机制涉及雌二醇与细胞内核受体（雌激素受体-α（ERα）和雌激素受体-β（ERβ））结合以促进蛋白质表达的变化。雌二醇也可以在几秒到几分钟内发挥作用，然而，这个时间尺度与基因组信号传导不一致。在大脑中，雌二醇迅速增强雌性大鼠纹状体中受刺激的多巴胺释放，并增强自发旋转行为。此外，雌二醇可迅速减弱 K+- 引起的透析液中 GABA 的增加。我们假设雌二醇在纹状体中的这些快速作用是由位于中型多刺 GABA 能神经元膜上的 ERα 介导的。该实验检验了纹状体中 ERα 的过度表达是否会增强雌二醇对旋转行为的影响以及 K+- 引起透析液中 GABA 的增加。将含有人 ERα cDNA (AAV.ERα) 的重组腺相关病毒 (AAV) 单侧纹状体注射到纹状体后，对切除卵巢的雌性大鼠进行旋转行为测试或进行微透析实验；对照组接受相同的载体进入纹状体以外的区域，或者接受含有人类碱性磷酸酶基因的AAV进入纹状体（AAV.ALP）。与对照组相比，在纹状体中接受 AAV.ERα 的动物表现出明显更大的雌二醇诱导的对侧旋转，并且表现出低剂量安非他明诱导的对侧旋转的行为敏感性。 ERα 过度表达还增强了雌二醇对 K+ 诱发的 GABA 释放的抑制作用，表明纹状体末端多巴胺释放的去抑制导致旋转行为增强。
Classical estrogen receptor signaling mechanisms involve estradiol binding to intracellular nuclear receptors (estrogen receptor-α (ERα) and estrogen receptor-β (ERβ)) to promote changes in protein expression. Estradiol can also exert effects within seconds to minutes, however, a timescale incongruent with genomic signaling. In the brain, estradiol rapidly potentiates stimulated dopamine release in the striatum of female rats and enhances spontaneous rotational behavior. Furthermore, estradiol rapidly attenuates the K+- evoked increase of GABA in dialysate. We hypothesize that these rapid effects of estradiol in the striatum are mediated by ERα located on the membrane of medium spiny GABAergic neurons. This experiment examined whether over-expression of ERα in the striatum would enhance the effect of estradiol on rotational behavior and the K+- evoked increase in GABA in dialysate. Ovariectomized female rats were tested for rotational behavior or underwent microdialysis experiments after unilateral intrastriatal injections of a recombinant adeno-associated virus (AAV) containing the human ERα cDNA (AAV.ERα) into the striatum; controls received either the same vector into areas outside the striatum or an AAV containing the human alkaline phosphatase gene into the striatum (AAV.ALP). Animals that received AAV.ERα in the striatum exhibited significantly greater estradiol-induced contralateral rotations compared to controls and exhibited behavioral sensitization of contralateral rotations induced by a low dose of amphetamine. ERα over-expression also enhanced the inhibitory effect of estradiol on K+- evoked GABA release suggesting that disinhibition of dopamine release from terminals in the striatum resulted in the enhanced rotational behavior.