背海马区 GABA 能紊乱与新生鼠缺氧缺血性脑损伤后氟烷致惊厥易感性的性别相关性。
Sex specific correlation between GABAergic disruption in the dorsal hippocampus and flurothyl seizure susceptibility after neonatal hypoxic-ischemic brain injury.
机构信息
Division of Neonatology, Department of Pediatrics, Johns Hopkins University School of Medicine, 600 North Wolf Street, Baltimore, MD 21287, USA.
Department of Neurology, Johns Hopkins University School of Medicine, 600 North Wolf Street, Baltimore, MD 21287, USA.
出版信息
Neurobiol Dis. 2021 Jan;148:105222. doi: 10.1016/j.nbd.2020.105222. Epub 2020 Dec 9.
Since neonatal hypoxia-ischemia (HI) disrupts the hippocampal (Hp) GABAergic network in the mouse and Hp injury in this model correlates with flurothyl seizure susceptibility only in male mice, we hypothesized that GABAergic disruption correlates with flurothyl seizure susceptibility in a sex-specific manner. C57BL6 mice were exposed to HI (Vannucci model) versus sham procedures at P10, randomized to normothermia (NT) or therapeutic hypothermia (TH), and subsequently underwent flurothyl seizure testing at P18. Only in male mice, Hp atrophy correlated with seizure susceptibility. The number of Hp parvalbumin positive interneurons (PVINs) decreased after HI in both sexes, but TH attenuated this deficit only in females. In males only, seizure susceptibility directly correlated with the number of PVINs, but not somatostatin or calretinin expressing INs. Hp GABA receptor subunit levels were decreased after HI, but unrelated to later seizure susceptibility. In contrast, Hp GABA receptor α1 subunit (GABARα1) levels were increased after HI. Adjusting the number of PV INs for their GABARα1 expression strengthened the correlation with seizure susceptibility in male mice. Thus, we identified a novel Hp sex-specific GABA-mediated mechanism of compensation after HI that correlates with flurothyl seizure susceptibility warranting further study to better understand potential clinical translation.
由于新生儿缺氧缺血（HI）会破坏小鼠海马（Hp）中的 GABA 能网络，并且该模型中的 Hp 损伤仅与雄性小鼠的氟烷惊厥易感性相关，因此我们假设 GABA 能破坏与氟烷惊厥易感性以性别特异性的方式相关。C57BL6 小鼠在 P10 时接受 HI（Vannucci 模型）与假手术处理，随机分为正常体温（NT）或治疗性低温（TH），随后在 P18 进行氟烷惊厥测试。只有雄性小鼠的 Hp 萎缩与惊厥易感性相关。HI 后，两性的 Hp 副甲状腺素阳性中间神经元（PVINs）数量减少，但仅在雌性中 TH 减弱了这种缺陷。只有在雄性中，惊厥易感性与 PVINs 的数量直接相关，而与生长抑素或钙结合蛋白表达的 INs 无关。HI 后 Hp GABA 受体亚基水平降低，但与随后的惊厥易感性无关。相比之下，HI 后 Hp GABA 受体 α1 亚基（GABARα1）水平增加。调整 PVINs 的数量以适应其 GABARα1 表达，可增强与雄性小鼠惊厥易感性的相关性。因此，我们确定了一种新的 Hp 性别特异性 GABA 介导的 HI 后代偿机制，与氟烷惊厥易感性相关，值得进一步研究以更好地理解潜在的临床转化。
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