Alteration of monoaminergic systems in the caudal medulla and its possible link to diurnal increase of apnea in a mouse model of Rett syndrome
Alteration of monoaminergic systems in the caudal medulla and its possible link to diurnal increase of apnea in a mouse model of Rett syndrome
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DOI：
10.2334/josnusd.22-0474
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发表时间：
2023-04-01
影响因子：
1.9
通讯作者：
Shirakawa, Tetsuo
中科院分区：
文献类型：
--
作者：
Hoshi, Manami;Ishiyama, Misa;Shirakawa, Tetsuo
目的：甲基 CpG 结合蛋白 2 (MeCP2) 缺陷 (Mecp2-/y) 小鼠表现出的呼吸暂停类似于雷特综合征 (RTT) 患者中观察到的呼吸异常。本研究旨在阐明 Mecp2-/y 小鼠是否表现出 RTT 中观察到的呼吸暂停的昼夜变化，以及 MeCP2 缺乏如何影响控制呼吸的单胺能系统。方法：在 7 周龄的 Mecp2-/y 小鼠中，评估呼吸暂停的 24 小时变化以及米那普仑（一种血清素/去甲肾上腺素再摄取抑制剂）对呼吸暂停的影响。计数尾髓质中囊泡单胺转运蛋白 2 (VMAT2) 免疫反应性斑点的数量。此外，通过 RT-qPCR 评估了丙戊酸 (VPA) 对小鼠腹外侧延髓中酪氨酸羟化酶 (TH) mRNA 表达的影响。结果：Mecp2-/y 小鼠在 12:12 小时光/暗环境下，在光相期间呼吸暂停发生频率更高，米那普仑在光相期间减少呼吸暂停，但在黑暗阶段则不然。 Mecp2-/y 小鼠中 VMAT2 免疫反应性斑点的数量减少。 VPA 处理显着增加 Mecp2-/y 小鼠中 TH mRNA 的表达。结论：Mecp2-/y 小鼠尾髓质单胺能系统的改变可能与光敏感的呼吸暂停昼间增加有关，单胺能神经传递的改善可以改善 Mecp2-/y 小鼠呼吸暂停的昼间增加。
Purpose: Methyl-CpG binding protein 2 (MeCP2)-deficient (Mecp2-/y) mice exhibit apneas that resemble respiratory abnormalities observed in Rett syndrome (RTT) patients. The present study aimed to clarify whether Mecp2-/y mice show diurnal variations in apnea as seen in RTT and how the MeCP2 deficiency affects monoaminergic systems that control breathing. Methods: In 7-week-old Mecp2-/y mice, 24 h variation of apnea and effects of milnacipran, a serotonin/noradrenaline reuptake inhibitor, on the apnea were evaluated. The number of vesicular monoamine transporter 2 (VMAT2)-immunoreactive puncta in the caudal medulla was counted. Further, the effects of valproate (VPA) on the expression of tyrosine hydroxylase (TH) mRNA in the ventrolateral medulla of mice were assessed by RT-qPCR. Results: Apnea occurred more frequently during the light phase under a 12:12 h light/dark environment in Mecp2-/y mice and milnacipran reduced apnea during the light phase but not during the dark phase. The number of VMAT2-immunoreactive puncta was reduced in Mecp2-/y mice. VPA treatment significantly increased TH mRNA expression in Mecp2-/y mice. Conclusion: Alteration of monoaminergic systems in the caudal medulla of Mecp2-/y mice is potentially relevant to the light-sensitive diurnal increase of apnea, and an improvement in monoaminergic neurotransmission can ameliorate the diurnal increase of apnea in Mecp2-/y mice.