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首页> 外文期刊>The European Journal of Neuroscience >Restored plasticity in a mouse model of neurofibromatosis type 1 via inhibition of hyperactive ERK and CREB.
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Restored plasticity in a mouse model of neurofibromatosis type 1 via inhibition of hyperactive ERK and CREB.

机译：通过抑制过度活跃的ERK和CREB，在1型神经纤维瘤病的小鼠模型中恢复了可塑性。

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Patients with neurofibromatosis type 1 (NF1), resulting from neurofibromin gene mutations, frequently suffer from deficits in learning and spatial memory. Mice heterozygous for functional deletion of the NF1 gene (NF1(+/-) mice) also exhibit compromised spatial learning, and deficits in early-stage hippocampal long-term potentiation (LTP). Neurofibromin is a multifunctional protein which acts in part as an inhibitory constraint on Ras signalling, and the deficits in early-stage LTP and spatial learning have been linked to Ras hyperactivation. However, the downstream targets of Ras hyperactivation that lead to cognitive disruption are unknown. The levels of activity of signalling molecules potentially downstream of Ras were therefore studied in NF1(+/-) mice. Elevated phospho-ERK (pERK) levels were observed in the hippocampi from NF1(+/-) mice, while phospho-Akt/PKB (pAkt) and phospho-eIF4E (peIF4E) levels were unchanged relative to wild-type mice. Hippocampal levels of phospho-CREB (pCREB) were also increased, suggesting potential changes in late-phase LTP in NF1(+/-) mice. Indeed, LTP was found to be impaired for at least 4 h following induction in NF1(+/-) mice, linking neurofibromin function with the long-term maintenance of LTP. Remarkably, U0126, an inhibitor of ERK activation, at doses which reduced the hyperactive pERK levels in NF1(+/-) mice to the levels observed in control mice, caused a reduction in the deficits in early-phase LTP and completely rescued the long-term LTP deficits. In contrast to the abundant evidence that reductions in ERK activity lead to impaired plasticity, these data indicate that ERK hyperactivation in a partial model of type 1 neurofibromatosis leads to deficits in long-lasting hippocampal plasticity.
机译：由神经纤维蛋白基因突变导致的1型神经纤维瘤病（NF1）患者经常遭受学习和空间记忆的缺陷。杂合子的功能缺失的NF1基因的小鼠（NF1（+/-）小鼠）还表现出空间学习受损和早期海马长期增强（LTP）的缺陷。神经纤维蛋白是一种多功能蛋白，部分作用是对Ras信号传导的抑制性约束，早期LTP和空间学习的缺陷与Ras过度活化有关。但是，导致认知障碍的Ras过度激活的下游目标是未知的。因此，在NF1（+/-）小鼠中研究了可能位于Ras下游的信号分子的活性水平。相对于野生型小鼠，在NF1（+/-）小鼠的海马体中观察到磷酸化ERK（pERK）水平升高，而磷酸化Akt / PKB（pAkt）和磷酸化eIF4E（peIF4E）水平则没有变化。海马的磷酸化CREB（pCREB）水平也增加，表明NF1（+/-）小鼠晚期LTP可能发生变化。确实，在NF1（+/-）小鼠中诱导后，LTP被削弱至少4小时，这将神经纤维蛋白功能与LTP的长期维持联系在一起。值得注意的是，ERK激活抑制剂U0126的剂量可将NF1（+/-）小鼠的过度活跃pERK水平降低至对照组小鼠的水平，从而减少了早期LTP的缺陷，并彻底挽救了长期长期LTP赤字。与大量证据表明ERK活性降低会导致可塑性受损相比，这些数据表明，在1型神经纤维瘤病的部分模型中ERK过度活化会导致海马持久塑性缺乏。

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