Sex difference in sensitivity to allopregnanolone neuroprotection in mice correlates with effect on spontaneous inhibitory post synaptic currents.
Sex difference in sensitivity to allopregnanolone neuroprotection in mice correlates with effect on spontaneous inhibitory post synaptic currents.
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DOI：
10.1016/j.neuropharm.2011.05.017
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发表时间：
2011-09
影响因子：
4.7
通讯作者：
Herson PS
中科院分区：
文献类型：
--
作者：
Kelley MH;Kuroiwa M;Taguchi N;Herson PS
别孕烯醇酮（ALLO）是一种神经类固醇，在大脑中具有许多功能，最显着的是神经保护和γ-氨基丁酸（GABA）神经传递的调节。使用心脏骤停和心肺复苏的小鼠模型，我们以前已经证明，ALLO保护小脑浦肯野细胞（PC）缺血的GABAA受体依赖性的方式。在这项研究中，我们检查了性别对ALLO神经保护的影响，观察到低剂量ALLO（2 mg/kg）在雌性中提供的神经保护作用大于雄性。在更高剂量的ALLO（8 mg/kg）下，两种性别均受到显著的缺血性损伤保护。使用急性小脑切片制备，从PC进行全细胞电压钳记录。自发抑制性突触后电流（IPSC）进行了分析，生理ALLO（10 nM）的反应是显着更大的女性PC相比，男性。与此相反，微型IPSC的记录，没有表现出性别差异，在响应ALLO，表明ALLO影响男性和女性的差异，通过结合突触后GABAA受体以外的机制。我们的结论是，女性大脑有更大的敏感性ALLO介导的增强GABA能神经传递，有助于增加神经保护。
Allopregnanolone (ALLO) is a neurosteroid that has many functions in the brain, most notably neuroprotection and modulation of gamma-amino butyric acid (GABA) neurotransmission. Using a mouse model of cardiac arrest and cardiopulmonary resuscitation, we have previously demonstrated that ALLO protects cerebellar Purkinje cells (PCs) from ischemia in a GABAA receptor-dependent manner. In this study we examined the effect of sex on ALLO neuroprotection, observing that low dose ALLO (2 mg/kg) provided greater neuroprotection in females compared to males. At a higher dose of ALLO (8 mg/kg), both sexes were significantly protected from ischemic damage. Using an acute cerebellar slice preparation, whole cell voltage clamp recordings were made from PCs. Spontaneous inhibitory postsynaptic currents (IPSCs) were analyzed and the response to physiological ALLO (10 nM) was significantly greater in female PCs compared to male. In contrast, recordings of miniature IPSCs, did not exhibit a sex difference in response to ALLO, suggesting that ALLO affects males and females differentially through a mechanism other than binding postsynaptic GABAA receptors. We conclude that the female brain has greater sensitivity to ALLO mediated potentiation of GABAergic neurotransmission, contributing to increased neuroprotection.