Center for Neuroscience Research, Children's Research Institute, Children's National Medical Center, Washington, DC, USA.
The George Washington University School of Medicine and Health Sciences, Washington, DC, USA.
Nat Commun. 2018 Aug 13;9(1):3235. doi: 10.1038/s41467-018-05656-w.
Premature infants are more likely to develop locomotor disorders than term infants. In a chronic sub-lethal hypoxia (Hx) mouse model of neonatal brain injury, we recently demonstrated the presence of cellular and physiological changes in the cerebellar white matter. We also observed Hx-induced delay in Purkinje cell (PC) arborization. However, the behavioral consequences of these cellular alterations remain unexplored. Using the Erasmus Ladder to study cerebellar behavior, we report the presence of locomotor malperformance and long-term cerebellar learning deficits in Hx mice. Optogenetics experiments in Hx mice reveal a profound reduction in spontaneous and photoevoked PC firing frequency. Finally, treatment with a gamma-aminobutyric acid (GABA) reuptake inhibitor partially rescues locomotor performance and improves PC firing. Our results demonstrate a long-term miscoordination phenotype characterized by locomotor malperformance and cerebellar learning deficits in a mouse model of neonatal brain injury. Our findings also implicate the developing GABA network as a potential therapeutic target for prematurity-related locomotor deficits.
早产儿比足月儿更容易出现运动障碍。在慢性亚致死性缺氧（Hx）新生鼠脑损伤模型中，我们最近发现在小脑白质中存在细胞和生理变化。我们还观察到 Hx 诱导的浦肯野细胞（PC）树突分支延迟。然而，这些细胞改变的行为后果仍未被探索。我们使用 Erasmus Ladder 研究小脑行为，报告了 Hx 小鼠存在运动功能障碍和长期小脑学习缺陷。Hx 小鼠的光遗传学实验显示自发性和光诱发 PC 放电频率的明显降低。最后，用γ-氨基丁酸（GABA）再摄取抑制剂治疗可部分恢复运动功能，并改善 PC 放电。我们的结果表明，在新生鼠脑损伤模型中存在长期的运动不协调表型，表现为运动功能障碍和小脑学习缺陷。我们的研究结果还表明，发育中的 GABA 网络可能是与早产相关的运动缺陷的潜在治疗靶点。
