Neocortical disruption and behavioral impairments in rats following in utero RNAi of candidate dyslexia risk gene Kiaa0319.
Neocortical disruption and behavioral impairments in rats following in utero RNAi of candidate dyslexia risk gene Kiaa0319.
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DOI：
10.1016/j.ijdevneu.2012.01.009
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发表时间：
2012-06
期刊：
影响因子：
--
通讯作者：
Fitch RH
中科院分区：
文献类型：
--
作者：
Szalkowski CE;Fiondella CG;Galaburda AM;Rosen GD;Loturco JJ;Fitch RH
在过去的十年中，一些基因已被确定为发育性阅读障碍的候选风险基因。最近使用动物模型和胚胎 RNA 干扰 (RNAi) 的研究表明，候选阅读障碍风险基因的一个子集——DYX1C1、ROBO1、DCDC2、KIAA0319——调节新皮质发育的关键参数，例如神经元迁移。例如，啮齿动物 DYX1C1 同源物的胚胎破坏会破坏神经元迁移，并导致快速听觉处理 (RAP) 和工作记忆缺陷——据报道，这些表型与发育性阅读障碍有关。在当前的研究中，我们使用改良的前脉冲抑制范例来评估雄性 Wistar 大鼠在子宫内针对 Kiaa0319 的 RNA 干扰后的声音辨别能力。我们还使用莫里斯水迷宫（MWM）和径向臂水迷宫评估了空间学习和工作记忆。我们发现，胚胎干扰该基因会导致新皮质神经元迁移中断，导致白质异位形成，并在一部分动物中形成海马发育不良。这些动物在处理复杂的声音刺激方面表现出缺陷，而那些患有海马畸形的动物表现出空间学习能力受损。在 Kiaa0319 RNAi 治疗的动物中没有检测到明显的工作记忆损伤。总而言之，这些结果表明 Kiaa0319 在胚胎发育过程中的神经元迁移中发挥作用，并且对该基因的早期干扰会导致一系列行为缺陷，包括快速听觉处理和简单空间学习的障碍。
Within the last decade several genes have been identified as candidate risk genes for developmental dyslexia. Recent research using animal models and embryonic RNA interference (RNAi) has shown that a subset of the candidate dyslexia risk genes—DYX1C1, ROBO1, DCDC2, KIAA0319—regulate critical parameters of neocortical development, such as neuronal migration. For example, embryonic disruption of the rodent homolog of DYX1C1 disrupts neuronal migration and produces deficits in rapid auditory processing (RAP) and working memory—phenotypes that have been reported to be associated with developmental dyslexia. In the current study we used a modified prepulse inhibition paradigm to assess acoustic discrimination abilities of male Wistar rats following in utero RNA interference targeting Kiaa0319. We also assessed spatial learning and working memory using a Morris water maze (MWM) and a radial arm water maze. We found that embryonic interference with this gene resulted in disrupted migration of neocortical neurons leading to formation of heterotopia in white matter, and to formation of hippocampal dysplasia in a subset of animals. These animals displayed deficits in processing complex acoustic stimuli, and those with hippocampal malformations exhibited impaired spatial learning abilities. No significant impairment in working memory was detected in the Kiaa0319 RNAi treated animals. Taken together, these results suggest that Kiaa0319 plays a role in neuronal migration during embryonic development, and that early interference with this gene results in an array of behavioral deficits including impairments in rapid auditory processing and simple spatial learning.
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影响因子：
5.2
作者：
Bishop DV
通讯作者：
Bishop DV
影响因子：
9.8
作者：
Cope, N;Harold, D;Williams, J
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Williams, J
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3.3
作者：
Burbridge, T. J.;Wang, Y.;Rosen, G. D.
通讯作者：
Rosen, G. D.
影响因子：
5.1
作者：
Fitch, R. Holly;Breslawski, Heather;Chrobak, James J.
通讯作者：
Chrobak, James J.
影响因子：
5.3
作者：
Chrobak, James J.;Hinman, James R.;Sabolek, Helen R.
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Sabolek, Helen R.