Institute for Neuroscience and Muscle Research, The Children's Hospital at Westmead, Locked Bag 4001, Westmead, Sydney, NSW, 2145, Australia.
J Neurol. 2013 Jan;260(1):214-20. doi: 10.1007/s00415-012-6620-5. Epub 2012 Aug 9.
Studies investigating behavior in mice with a heterozygous null mutation of the NF1 gene (Nf1 (+/-)) have provided critical insights into the molecular and cellular mechanisms underlying cognitive impairments associated with neurofibromatosis type 1 (NF1). Hyperactivation of the Ras-MAPK signaling cascade, which results in increased GABA-mediated inhibition and significantly reduced long-term potentiation, has been proposed as a core mechanism underlying Nf1 (+/-) mice deficits in visuospatial learning and attention. This assertion has been reinforced by preclinical trials that reveal that these impairments can be rescued both at a cognitive and cellular level. We attempted to demonstrate a phenotypic parallel between Nf1 (+/-) mice and children with NF1 using a well-validated measure of visuospatial learning. Children with NF1 (n = 71) and healthy controls (n = 29) were assessed on a computerized paired associate learning task. Interrelationships between visuospatial learning and other cognitive abilities that may influence performance, such as intelligence, attention and visuospatial function, were explored. Children with NF1 displayed significant impairments in visuospatial learning, with reduced initial retention and poorer learning across repeated trials. Importantly, we demonstrated that visuospatial learning was inferior in NF1 even after accounting for group differences in intelligence, sustained attention and visuospatial abilities. We have thus identified impaired visuospatial learning as a core phenotypic feature in children with NF1. These findings imply that hippocampal-based learning networks are dysfunctional in children with NF1 and provide validation for a primary outcome measure for clinical trials aiming to correct aberrant Ras signaling.
研究调查了 NF1 基因杂合缺失突变（Nf1（ +/- ））的小鼠行为，为神经纤维瘤病 1 型（NF1）相关认知障碍的分子和细胞机制提供了重要见解。Ras-MAPK 信号级联的过度激活导致 GABA 介导的抑制增加和长时程增强显著减少，被认为是 Nf1（ +/- ）小鼠在视觉空间学习和注意力缺陷的核心机制。这一断言得到了临床前试验的支持，这些试验表明，这些缺陷可以在认知和细胞水平上得到挽救。我们试图使用一种经过充分验证的视觉空间学习测量方法，证明 Nf1（ +/- ）小鼠和 NF1 患儿之间存在表型平行。对 71 名 NF1 患儿和 29 名健康对照者进行了计算机化的配对联想学习任务评估。探索了视觉空间学习与可能影响表现的其他认知能力（如智力、注意力和视觉空间功能）之间的相互关系。NF1 患儿在视觉空间学习方面存在显著缺陷，初始保留和多次试验中的学习较差。重要的是，我们证明即使考虑到 NF1 组在智力、持续注意力和视觉空间能力方面的差异，NF1 患儿的视觉空间学习仍然较差。因此，我们确定了视觉空间学习受损是 NF1 患儿的核心表型特征之一。这些发现意味着 NF1 患儿的海马基学习网络功能失调，并为旨在纠正异常 Ras 信号的临床试验提供了主要的结果测量。
