Multi functional studies of candidate dyslexia susceptibility genes in the rat

拟议的计划项目是研究一种独特的发展性学习障碍大鼠模型，该模型使用 用发育神经生物学、结构解剖学和行为学的方法对三者的功能进行分析 候选阅读障碍易感基因(CDSG)。阅读困难症患者脑内神经病理学研究 以前的动物模型已经强调了局灶性神经元移行缺陷和 一些阅读障碍患者的发育可塑性。CDSGs的发现向我们提出了分析 这种遗传变异对大脑发育、结构和学习行为的影响 残疾。使用我们实验室开发的宫内电穿孔方法，我们将转染成 脑室区域的年轻神经元短发夹状RNA或靶向过度表达的结构 CDSG Dyxicl、KIAA0319或DCDC2大鼠的同源物。我们已经看到，这个程序导致了 对神经元的异常迁移，改变神经元的形态，并导致未接触的继发性效应 相邻的神经元，从而产生一幅让人联想到阅读困难的大脑的图片。有趣的行为 也可以看到变化。项目I(J.J.LoTurco，PI)将分析Dyxicl与基因的交互作用 已知的涉及过程延伸、核运动和细胞黏附的分子通路， Dyxicl上的区域对功能至关重要。项目II(A.M.Galaburda，PI)将描述解剖学 与击倒或连接相关的变化(皮质结构、细胞身份、形态和连接性) CDSGs基因过表达。项目III(H.Fitch，PI)将揭示CDSG的行为后果 干扰(听觉处理和学习)，并将试图改善这些基因的影响 通过行为干预进行操纵。这三个互动项目将由一个 管理核心，子宫电穿孔核心，神经组织学，形态计量学和数据 处理核心。更好地理解CDSG的职能将有助于更广泛地了解 正常大脑发育的机制和发育性阅读障碍的异常，但 还提供了更早发现、基于生物学的亚型和改进治疗的可能性。

The proposed Program Project is to study a unique rat model of developmental learning disability that uses methods of developmental neurobiology, structural anatomy, and behavior to analyze the functions of three candidate dyslexia susceptibility genes (CDSGs). Neuropathologic studies in human dyslexic brains and previous animal models have underscored the importance of focal neuronal migration defects and developmental plasticity for some of the dyslexic deficits. The discovery of CDSGs challenges us to analyze the effects of this genetic variation on brain development, structure, and behavior with respect to learning disability. Using an in utero electroporation method developed in our laboratories, we will transfect into young neurons in the ventricular zone short hairpin RNAs or over-expression constructs targeted against homologs in the rat of CDSG Dyxicl, Kiaa0319, or Dcdc2. We have already seen that this procedure leads to abnormal neuronal migration, alters neuronal morphology, and causes secondary effects in untouched neighboring neurons, thus producing a picture reminiscent of dyslexic brains. Interesting behavioral alterations are also seen. Project I (J.J. LoTurco, PI) will analyze Dyxicl's interaction with genes with known molecular pathways involved in process extension, nuclear movement, and cell adhesion, the domains on the Dyxicl critical to function. Project II (A.M. Galaburda, PI) will characterize anatomic changes (cortical architecture, cell identity, morphology, and connectivity) associated with knockdown or overexpression of CDSGs. Project III (H. Fitch, PI) will uncover behavioral consequences of CDSG disruption (auditory processing and learning), and will attempt to ameliorate the effects of these genetic manipulations by behavioral interventions. The three interactive projects will be supported by an Administrative Core, an In Utero Electroporation Core, and a Neurohistology, Morphometry, and Data Processing Core. A better understanding of the functions of CDSGs will shed a broader light on mechanisms of normal brain development and on the abnormalities seen in developmental dyslexia, but also offering the possibility of earlier detection, biologically-based subtyping, and improved treatment.