Multi functional studies of candidate dyslexia susceptibility genes in the rat

描述（由申请人提供）：本计划项目旨在研究一种独特的发育性学习障碍大鼠模型，该模型使用发育神经生物学，结构解剖学和行为学方法来分析三种候选阅读障碍易感基因（CDSGs）的功能。 在人类睡眠障碍大脑和以前的动物模型的神经病理学研究强调了局灶性神经元迁移缺陷和发育可塑性的一些睡眠障碍赤字的重要性。 CDSGs的发现挑战我们分析这种遗传变异对大脑发育，结构和行为的影响，与学习障碍有关。 使用他们实验室开发的子宫内电穿孔方法，研究人员将在心室区的年轻神经元中插入针对大鼠CDSG Dyx1c1，Kiaa0319或Dcdc2同源物的短发夹RNA或过表达构建体。 他们已经看到，这个过程会导致异常的神经元迁移，改变神经元形态，并在未受影响的邻近神经元中引起继发性影响，从而产生一种让人联想到睡眠障碍的大脑的图像。 还可以看到有趣的行为变化。 项目I将分析Dyx1c1与已知分子途径的基因的相互作用，这些分子途径涉及过程延伸、核运动和细胞粘附，这些结构域对Dyx1c1的功能至关重要。 项目II将描述与CDSG敲低或过表达相关的解剖学变化（皮质结构、细胞特性、形态学和连接性）。 项目III将揭示CDSG中断（听觉处理和学习）的行为后果，并试图通过行为干预来改善这些遗传操作的影响。 这三个互动项目将由一个管理核心，一个子宫内电穿孔核心，和一个神经组织学，形态测量学和数据处理核心支持。 更好地了解CDSGs的功能将更广泛地了解正常大脑发育的机制和发育性阅读障碍中的异常，但也提供了早期检测，基于生物学的亚型和改善治疗的可能性。 相关性：人类疾病的动物模型传统上有助于推动该领域的发展，并导致更好的诊断和治疗方法。 一般来说，学习障碍的动物模型很少，而阅读障碍的动物模型只有一种。 从拟议的工作结果是倾向于帮助我们更全面地了解人类阅读障碍，更准确地诊断，并确定更好的治疗方式。

DESCRIPTION (provided by applicant): This 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 their laboratories, the investigators will transfect into young neurons in the ventricular zone short hairpin RNAs or overexpression constructs targeted against homologs in the rat of CDSG Dyx1c1, Kiaa0319, or Dcdc2. They 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 will analyze Dyx1c1's interaction with genes with known molecular pathways involved in process extension, nuclear movement, and cell adhesion, the domains on the Dyx1c1 critical to function. Project II will characterize anatomic changes (cortical architecture, cell identity, morphology, and connectivity) associated with knockdown or overexpression of CDSGs. Project III 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. RELEVANCE: Animal models of human disorders have traditionally been helpful for moving the field forward and leading to better diagnostic and treatment approaches. There are few animal models for learning disorders in general, and only one for dyslexia. Results from the proposed work are apt to help us understand human dyslexia more fully, diagnose it more accurately, and define better treatment modalities.