Role of GABA in central respiratory control in mice lacking GABA-synthesizing enzyme 67-kDa isoform of glutamic acid decarboxylase

GABA 在缺乏 GABA 合成酶谷氨酸脱羧酶 67-kDa 亚型的小鼠中枢呼吸控制中的作用

• 批准号: 13680882
• 负责人: KUWANA Shin-ichi
• 金额: $ 0.96万
• 依托单位: Teikyo University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13680882/
• 关键词: GABA; Respiration; GAD67; Knock-out mice; Respiratory rhythm; Brainstem-spinal cord; Neuronal network; Neonatal mice; GAD; 高炭酸ガス応答; 低酸素応答; 口蓋裂

To examine the role of GABA in the respiratory rhythm and pattern generation in neonatal mice, we analyzed the function of the respiratory control system of 67-kDa isoform of glutamic acid decarboxylase (GAD67)-deficient neonatal mice. In these mutant (GAD67-/-) mice, GABA levels in the brainstem were reduced to about 30 % of those in wild-type (GAD67+/+) mice. In in vivo preparations, ventilatory parameters were analyzed by whole body plethysmography and electromyography of intercostal muscles. GAD67-/-mice exhibited abnormal respiratory' patterns, i.e., irregular respiratory rhythm, and periodic gasp-like respiration followed by shallow breathing with short inspiratory duration and apnea. In in vitro GAD67-/-brainstem-spinal cord preparations, inspiratory C4 burst duration was shorter than that in GAD67+/+ preparations. Whole cell recordings revealed that activities of inspiratory neurons in the ventral medulla of GAD67-/-mice were characterized by a short depolarization period and a paucity of firing during the inspiratory phase. Superfusion of the in vitro GAD67-/-preparation with 10 g M GABA prolongedC4 burst duration and partly restored a normal pattern of inspiration, although the restoration was limited. These results indicate that reduced GABA levels during the perinatal period induce malfunction in the respiratory control system. We suggest that GABAergic transmission is not essential for basic respiratory rhythm generation but plays an important role in the maintenance of regular respiratory rhythm and normal inspiratory pattern in neonatal mice.

为了研究 GABA 在新生小鼠呼吸节律和模式生成中的作用，我们分析了 67-kDa 谷氨酸脱羧酶 (GAD67) 缺陷的新生小鼠呼吸控制系统的功能。在这些突变型 (GAD67-/-) 小鼠中，脑干中的 GABA 水平降低至野生型 (GAD67+/+) 小鼠的约 30%。在体内制剂中，通过全身体积描记法和肋间肌肌电图分析通气参数。 GAD67-/-小鼠表现出异常的呼吸模式，即呼吸节律不规则，周期性喘息样呼吸，随后是吸气持续时间短的浅呼吸和呼吸暂停。在体外 GAD67-/-脑干脊髓制剂中，吸气 C4 爆发持续时间比 GAD67+/+ 制剂中的短。全细胞记录显示，GAD67-/-小鼠腹侧延髓中吸气神经元的活动特征是吸气相期间去极化周期短且放电很少。体外 GAD67-/- 制剂与 10 g M GABA 的灌注延长了 C4 爆发持续时间，并部分恢复了正常的吸气模式，尽管恢复是有限的。这些结果表明，围产期 GABA 水平降低会导致呼吸控制系统出现故障。我们认为，GABA能传递对于基本呼吸节律的产生并不是必需的，但在维持新生小鼠的规则呼吸节律和正常吸气模式中起着重要作用。

项目成果

Kuwana Shun-ichi: "Role of GABA in central respiratory control studied in mice Lacking GABA synthesizing enzyme 67-kDa isoform of glutamic acid decarboxylase."Adv Exp Med Biol. (in press). (2004)

Kuwana Shun-ichi：“在缺乏 GABA 合成酶 67-kDa 谷氨酸脱羧酶亚型的小鼠中研究 GABA 在中枢呼吸控制中的作用。”Adv Exp Med Biol。

Okada Y, Chen Z, Jiang W, Kuwana S, Eldridge FL: "Anatomical arrangement of hypercapnia-activated cells in the superficial ventral medulla of rats"J Appl Physiol. 93. 427-439 (2002)

Okada Y、Chen Z、Jiang W、Kuwana S、Eldridge FL：“大鼠浅层腹侧髓质中高碳酸血症激活细胞的解剖学排列”J Appl Physiol。

Kuwana S, Okada Y, Sugawara Y, Obata K: "Role of GABA in central respiratory control studied in mice lacking GABA-synthesizing enzyme 67-kDa isoform of glutamic acid decarboxylase"Adv Exp Med Biol. (in press). (2004)

Kuwana S、Okada Y、Sugara Y、Obata K：“在缺乏 GABA 合成酶 67-kDa 谷氨酸脱羧酶亚型的小鼠中研究 GABA 在中枢呼吸控制中的作用”Adv Exp Med Biol。

Kuwana Shun-ichi: "Role of GABA in the hypoxic ventilatory depression : studies in GAD67-deficient neonatal mice"Neuroscience Res.. 26(Suppl)(in press). (2002)

桑名俊一：“GABA 在缺氧通气抑制中的作用：GAD67 缺陷新生小鼠的研究”Neuroscience Res.. 26（增刊）（印刷中）。

Okada Yasumasa: "Electrical stimulation of the rabbit pulmonary artery increases respiratory output."Respiratory Physiology & Neurobiology. (in press). (2004)

冈田康正：“电刺激兔子肺动脉会增加呼吸输出量。”呼吸生理学