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

为了研究GABA在新生小鼠呼吸节律和模式生成中的作用，我们分析了谷氨酸脱羧酶（GAD67）缺失的新生小鼠67-kDa亚型的呼吸控制系统的功能。在这些突变（GAD67-/-）小鼠中，脑干中的GABA水平降低到野生型（GAD67+/+）小鼠的30%左右。在体内制剂中，通过全身体积脉搏图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，即呼吸节奏不规则，周期性气样呼吸，呼吸浅，吸气时间短，呼吸暂停。在体外GAD67-/-脑干-脊髓制剂中，吸气性C4爆发持续时间比GAD67+/+制剂短。全细胞记录显示，GAD67-/-小鼠腹侧髓质吸气神经元的活动具有去极化期短、吸气期放电少的特点。10 g M GABA灌注GAD67-/-体外制剂可延长dc4爆发持续时间，部分恢复正常的灌注模式，但恢复程度有限。这些结果表明围产期GABA水平的降低会引起呼吸控制系统的功能障碍。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，但在维持新生小鼠正常呼吸节律和正常吸气模式中起重要作用。

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.