Department of Applied Science, William & Mary, Williamsburg, VA 23185, USA.
Department of Applied Science, William & Mary, Williamsburg, VA 23185, USA.
Cell Rep. 2023 Aug 29;42(8):113000. doi: 10.1016/j.celrep.2023.113000. Epub 2023 Aug 16.
Inspiration is the inexorable active phase of breathing. The brainstem pre-Bötzinger complex (preBötC) gives rise to inspiratory neural rhythm, but its underlying cellular and ionic bases remain unclear. The long-standing "pacemaker hypothesis" posits that the persistent Na current (I) that gives rise to bursting-pacemaker properties in preBötC interneurons is essential for rhythmogenesis. We tested the pacemaker hypothesis by conditionally knocking out and knocking down the Scn8a (Na1.6 [voltage-gated sodium channel 1.6]) gene in core rhythmogenic preBötC neurons. Deleting Scn8a substantially decreases the I and abolishes bursting-pacemaker activity, which slows inspiratory rhythm in vitro and negatively impacts the postnatal development of ventilation. Diminishing Scn8a via genetic interference has no impact on breathing in adult mice. We argue that the Scn8a-mediated I is not obligatory but that it influences the development and rhythmic function of the preBötC. The ubiquity of the I in respiratory brainstem interneurons could underlie breathing-related behaviors such as neonatal phonation or rhythmogenesis in different physiological conditions.
灵感是呼吸不可阻挡的主动阶段。脑桥 Pre-Bötzinger 复合体（preBötC）产生吸气神经节律，但其潜在的细胞和离子基础仍不清楚。长期存在的“起搏器假说”假设，在 preBötC 中间神经元中产生爆发-起搏器特性的持续 Na 电流（I）对于节律发生至关重要。我们通过条件敲除和敲低核心节律生成 preBötC 神经元中的 Scn8a（Na1.6 [电压门控钠离子通道 1.6]）基因来测试起搏器假说。删除 Scn8a 会大大降低 I 并消除爆发-起搏器活动，从而减缓体外吸气节律，并对通气的出生后发育产生负面影响。通过遗传干扰减少 Scn8a 对成年小鼠的呼吸没有影响。我们认为，Scn8a 介导的 I 不是必需的，但它会影响 preBötC 的发育和节律功能。I 在呼吸性脑干中间神经元中的普遍性可能是新生儿发声或不同生理条件下节律发生等与呼吸相关行为的基础。
