EGF Treatment Improves Motor Behavior and Cortical GABAergic Function in the R6/2 Mouse Model of Huntington's Disease
EGF Treatment Improves Motor Behavior and Cortical GABAergic Function in the R6/2 Mouse Model of Huntington's Disease
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DOI：
10.1007/s12035-019-1634-y
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发表时间：
2019-11-01
影响因子：
5.1
通讯作者：
Tai, Leon M.
中科院分区：
文献类型：
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作者：
Marottoli, Felecia M.;Priego, Mercedes;Tai, Leon M.
最近的证据表明，突变型亨廷顿蛋白（polyQ-htt）对表皮生长因子（EGF）信号传导的破坏可能通过多种机制（包括脑血管功能障碍）导致亨廷顿病（HD）中观察到的行为缺陷的发生。然而，EGF信号传导是否调节HD病理学的发展和相关的行为障碍仍不清楚。为了深入了解这个问题，我们使用了HD的R6/2小鼠模型来评估慢性EGF治疗对行为、脑血管和皮质神经元功能的影响。我们发现用低剂量EGF（300 μ g/kg，i. p.）持续6周足以有效改善R6/2小鼠的运动行为并降低死亡率。EGF治疗的这些有益效果与脑血管渗漏的变化无关，考虑到EGF改善其他神经退行性疾病中的这种缺陷，这一结果令人惊讶。相反，EGF对R6/2小鼠行为的有益作用伴随着皮质GABA能功能的显著改善。由于在HD中皮质回路中的GABA能传递被破坏，这些新数据表明在HD进展中EGF信号传导缺陷和GABA能功能障碍之间存在潜在的机制联系。
Recent evidence indicates that disruption of epidermal growth factor (EGF) signaling by mutant huntingtin (polyQ-htt) may contribute to the onset of behavioral deficits observed in Huntington's disease (HD) through a variety of mechanisms, including cerebrovascular dysfunction. Yet, whether EGF signaling modulates the development of HD pathology and the associated behavioral impairments remain unclear. To gain insight on this issue, we used the R6/2 mouse model of HD to assess the impact of chronic EGF treatment on behavior, and cerebrovascular and cortical neuronal functions. We found that bi-weekly treatment with a low dose of EGF (300 mu g/kg, i.p.) for 6 weeks was sufficient to effectively improve motor behavior in R6/2 mice and diminish mortality, compared to vehicle-treated littermates. These beneficial effects of EGF treatment were dissociated from changes in cerebrovascular leakiness, a result that was surprising given that EGF ameliorates this deficit in other neurodegenerative diseases. Rather, the beneficial effect of EGF on R6/2 mice behavior was concomitant with a marked amelioration of cortical GABAergic function. As GABAergic transmission in cortical circuits is disrupted in HD, these novel data suggest a potential mechanistic link between deficits in EGF signaling and GABAergic dysfunction in the progression of HD.