Department of Physiology, The University of Arizona, Tucson, Arizona.
Department of Neuroscience, The University of Arizona, Tucson, Arizona.
J Neurophysiol. 2022 Dec 1;128(6):1483-1500. doi: 10.1152/jn.00397.2022. Epub 2022 Nov 9.
Regulation of GABAergic signaling through nicotinic acetylcholine receptor (nAChR) activation is critical for neuronal development. Here, we test the hypothesis that chronic episodic developmental nicotine exposure (eDNE) disrupts GABAergic signaling, leading to dysfunction of hypoglossal motor neurons (XIIMNs), which innervate the tongue muscles. We studied control and eDNE pups at two developmentally vulnerable age ranges: postnatal days (P)1-5 and P10-12. The amplitude and frequency of spontaneous and miniature inhibitory postsynaptic currents (sIPSCs, mIPSCs) at baseline were not altered by eDNE at either age. In contrast, eDNE increased GABAR-α1 receptor expression on XIIMNs and, in the older group, the postsynaptic response to muscimol (GABA receptor agonist). Activation of nAChRs with exogenous nicotine increased the frequency of GABAergic sIPSCs in control and eDNE neurons at P1-5. By P10-12, acute nicotine increased sIPSC frequency in eDNE but not control neurons. In vivo experiments showed that the breathing-related activation of tongue muscles, which are innervated by XIIMNs, is reduced at P10-12. This effect was partially mitigated by subcutaneous muscimol, but only in the eDNE pups. Taken together, these data indicate that eDNE alters GABAergic transmission to XIIMNs at a critical developmental age, and this is expressed as reduced breathing-related drive to XIIMNs in vivo. Here, we provide a thorough assessment of the effects of nicotine exposure on GABAergic synaptic transmission, from the cellular to the systems level. This work makes significant advances in our understanding of the impact of nicotine exposure during development on GABAergic neurotransmission within the respiratory network and the potential role this plays in the excitatory/inhibitory imbalance that is thought to be an important mechanism underlying neonatal breathing disorders, including sudden infant death syndrome.
通过烟碱型乙酰胆碱受体 (nAChR) 激活调节 GABA 能信号对于神经元发育至关重要。在这里，我们检验了这样一个假设，即慢性偶发性发育性尼古丁暴露 (eDNE) 会破坏 GABA 能信号，导致舌下运动神经元 (XIIMNs) 功能障碍，这些神经元支配舌肌。我们研究了控制组和 eDNE 幼崽在两个发育易损期：出生后第 1-5 天和第 10-12 天。eDNE 在这两个年龄阶段均未改变基础状态下自发性和微小抑制性突触后电流 (sIPSCs，mIPSCs) 的幅度和频率。相比之下，eDNE 增加了 XIIMN 上的 GABAR-α1 受体表达，并且在年龄较大的组中，对 muscimol（GABA 受体激动剂）的突触后反应增加。用外源性尼古丁激活 nAChR 可增加对照组和 eDNE 神经元在 P1-5 时 GABA 能 sIPSCs 的频率。到 P10-12 时，急性尼古丁增加了 eDNE 而非对照组神经元的 sIPSC 频率。体内实验表明，由 XIIMN 支配的舌肌的呼吸相关激活在 P10-12 时减少。这种效应部分被皮下 muscimol 缓解，但仅在 eDNE 幼崽中。综上所述，这些数据表明，eDNE 在关键发育年龄改变了 XIIMNs 的 GABA 能传递，这表现为体内 XIIMNs 的呼吸相关驱动减少。在这里，我们从细胞到系统水平全面评估了尼古丁暴露对 GABA 能突触传递的影响。这项工作在理解发育期间尼古丁暴露对呼吸网络内 GABA 能神经传递的影响方面取得了重大进展，并且可能在兴奋性/抑制性失衡中发挥作用，这被认为是新生儿呼吸障碍的重要机制，包括婴儿猝死综合征。
