Reduced striatal dopamine underlies the attention system dysfunction in neurofibromatosis-1 mutant mice
Reduced striatal dopamine underlies the attention system dysfunction in neurofibromatosis-1 mutant mice
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DOI：
10.1093/hmg/ddq382
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发表时间：
2010-11-15
影响因子：
3.5
通讯作者：
Gutmann, David H.
中科院分区：
文献类型：
--
作者：
Brown, Jacquelyn A.;Emnett, Ryan J.;Gutmann, David H.
学习和行为异常是神经纤维瘤病 1 (NF1) 遗传性癌症综合征儿童最常见的临床问题之一。最近使用 Nf1 基因工程小鼠 (GEM) 进行的研究对于部分阐明这些认知缺陷背后的细胞和分子缺陷具有指导意义。然而，目前还没有模型能够揭示 1 型神经纤维瘤病儿童中更常见的注意力系统异常现象。使用 Nf1 视神经胶质瘤 (OPG) GEM 模型，我们报告了非选择性和选择性注意力的新缺陷，而没有伴随的多动表型。具体来说，Nf1 OPG 小鼠对新物体和环境刺激的反应表现出减少。与患有 NF1 的儿童类似，这些小鼠的注意力系统功能障碍通过哌甲酯 (MPH) 治疗得到逆转，这表明大脑儿茶酚胺稳态存在缺陷。我们进一步证明，这种注意力系统异常是纹状体中多巴胺 (DA) 水平降低的结果，在 MPH 或左旋多巴给药后，多巴胺 (DA) 水平会恢复正常。 Nf1 OPG 小鼠纹状体 DA 水平的降低与纹状体酪氨酸羟化酶（DA 合成中的限速酶）表达的减少有关，而黑质中没有任何相关的多巴胺能细胞损失。此外，我们在体外证明了 Nf1+/- 多巴胺能神经元生长锥区域和神经突延伸的细胞自主缺陷，这导致体内 Nf1 OPG 小鼠向纹状体的多巴胺能细胞投射减少。总的来说，这些数据表明 DA 稳态异常是与 NF1 儿童相关的 Nf1 GEM 注意力系统功能障碍的主要生化缺陷。
Learning and behavioral abnormalities are among the most common clinical problems in children with the neurofibromatosis-1 (NF1) inherited cancer syndrome. Recent studies using Nf1 genetically engineered mice (GEM) have been instructive for partly elucidating the cellular and molecular defects underlying these cognitive deficits; however, no current model has shed light on the more frequently encountered attention system abnormalities seen in children with NF1. Using an Nf1 optic glioma (OPG) GEM model, we report novel defects in non-selective and selective attention without an accompanying hyperactivity phenotype. Specifically, Nf1 OPG mice exhibit reduced rearing in response to novel objects and environmental stimuli. Similar to children with NF1, the attention system dysfunction in these mice is reversed by treatment with methylphenidate (MPH), suggesting a defect in brain catecholamine homeostasis. We further demonstrate that this attention system abnormality is the consequence of reduced dopamine (DA) levels in the striatum, which is normalized following either MPH or L-dopa administration. The reduction in striatal DA levels in Nf1 OPG mice is associated with reduced striatal expression of tyrosine hydroxylase, the rate-limited enzyme in DA synthesis, without any associated dopaminergic cell loss in the substantia nigra. Moreover, we demonstrate a cell-autonomous defect in Nf1+/- dopaminergic neuron growth cone areas and neurite extension in vitro, which results in decreased dopaminergic cell projections to the striatum in Nf1 OPG mice in vivo. Collectively, these data establish abnormal DA homeostasis as the primary biochemical defect underlying the attention system dysfunction in Nf1 GEM relevant to children with NF1.