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首页> 外文学位 >Nf1-deficient mice display social learning deficits that are rescued by the deletion of PAK1 gene.
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Nf1-deficient mice display social learning deficits that are rescued by the deletion of PAK1 gene.

机译：Nf1缺陷小鼠表现出社交学习缺陷，可以通过删除PAK1基因来挽救。

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摘要

Neurofibromatosis type 1 (NF1) is a neurocutaneous disorder that affects roughly 1 in 3500 individuals. In addition to physical features (e.g., neurofibromas), developmental disorders are also common that can affect cognition, learning, attention and social function. The NF1 gene encodes neurofibromin, a GTPase activating protein (GAP)-like protein that negatively regulates Ras GTPase activation. Mutation at the NF1 locus increases the output of MAPK and PI3K signal transduction from the cellular membrane to the nucleus. Similar to humans, Nf1+/- mice show spatial learning abnormalities that are potentially correlated with increases in GABA-mediated inhibition and deficits in long-term potentiation in the hippocampus. Here, we demonstrate for the first time that Nf1 +/- mice exhibit a selective loss of long-term social learning / memory and increased GABAergic inhibition in the basolateral amygdala, a critical brain region for regulating social behaviors. Next, utilizing a genetic intercross, we show that the co-deletion of p21-activated kinase type 1 ( Pak1-/-), which positively regulates MAPK activation, restores Nf1+/--dependent MAPK hyperactivation in neurons cultured from the frontal cortex. We found that the co-deletion of Pak1 in Nf1+/- mice ( Nf1+/- / Pak1-/-) also restores the deficits in long-term social learning / memory seen in Nf1+/- mice and normalizes the increases in GABA-mediated inhibition in the BLA, as compared to Nf1+/- mice. Together, these findings establish a role for Nf1 and Pak1 genes in the regulation of social learning in Nf1-deficient mice. Furthermore, proteomic studies identify dysregulation of F-actin and microtubule dynamics in the prefrontal cortex, and implicate proteins associated with vesicular release as well as neurite formation and outgrowth (e.g., LSAMP, STXBP1, DREB). In the BLA, disintegrin and metalloproteinase domain-containing protein 22 (ADAM22) was identified, and ADAM22 may play a role in the regulation of AMPA receptors. Finally, due to the increased co-occurrence of NF1 and autism, these findings may also have important implications for the pathology and treatment of NF1-related social deficits and some forms of autism.
机译：1型神经纤维瘤病（NF1）是一种神经皮肤疾病，大约每3500个人中有1人受到影响。除了身体特征（例如神经纤维瘤）外，发育障碍也是常见的，会影响认知，学习，注意力和社会功能。 NF1基因编码神经纤维蛋白，一种负调节Ras GTPase激活的GTPase激活蛋白（GAP）样蛋白。 NF1基因座处的突变增加了从细胞膜到细胞核的MAPK和PI3K信号转导的输出。与人类相似，Nf1 +/-小鼠显示出空间学习异常，这可能与GABA介导的抑制作用增加以及海马的长期增强功能缺陷有关。在这里，我们首次证明Nf1 +/-小鼠在基底外侧杏仁核（调节社交行为的关键大脑区域）中表现出选择性的长期社会学习/记忆丧失和GABA能抑制增加。接下来，利用遗传交叉，我们显示正调控MAPK激活的p21激活的1型激酶（Pak1-/-）的共缺失可恢复额叶皮层培养的神经元中Nf1 +/-依赖的MAPK过度激活。我们发现在Nf1 +/-小鼠（Nf1 +/- / Pak1-/-）中共删除Pak1也可以恢复在Nf1 +/-小鼠中看到的长期社会学习/记忆缺陷，并使GABA介导的增加正常化与Nf1 +/-小鼠相比，BLA具有抑制作用。在一起，这些发现建立了Nf1和Pak1基因在Nf1缺陷小鼠社交学习调控中的作用。此外，蛋白质组学研究发现前额叶皮层中F-肌动蛋白的失调和微管动力学异常，并暗示与囊泡释放以及神经突形成和长出相关的蛋白质（例如LSAMP，STXBP1，DREB）。在BLA中，鉴定出含有整合素和金属蛋白酶结构域的蛋白22（ADAM22），ADAM22可能在AMPA受体的调节中起作用。最后，由于NF1和自闭症的并发增加，这些发现也可能对与NF1相关的社会缺陷和某些形式的自闭症的病理学和治疗产生重要影响。

著录项

  • 作者

    Spence, John Paul.;

  • 作者单位

    Indiana University.;

  • 授予单位 Indiana University.;
  • 学科 Biology Neuroscience.;Psychology Psychobiology.
  • 学位 Ph.D.
  • 年度 2010
  • 页码 176 p.
  • 总页数 176
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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