Multi functional studies of candidate dyslexia susceptibility genes in the rat

描述（由申请人提供）：本项目拟研究一种独特的发展性学习障碍大鼠模型，利用发育神经生物学、结构解剖学和行为学等方法分析三种候选阅读障碍易感基因（CDSGs）的功能。人类失读症大脑的神经病理学研究和先前的动物模型强调了局灶性神经元迁移缺陷和发育可塑性对一些失读症缺陷的重要性。CDSGs的发现挑战了我们分析这种遗传变异对大脑发育、结构和学习障碍行为的影响。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转染短发夹rna或针对大鼠CDSG Dyx1c1， Kiaa0319或Dcdc2同源物的过表达构建物。他们已经看到，这一过程会导致异常的神经元迁移，改变神经元形态，并对未受影响的相邻神经元造成继发性影响，从而产生一幅让人联想起阅读障碍大脑的画面。有趣的行为变化也被观察到。项目一将分析Dyx1c1与已知分子通路基因的相互作用，这些通路涉及过程延伸、核运动和细胞粘附，Dyx1c1上的结构域对功能至关重要。项目II将描述与CDSGs敲低或过表达相关的解剖变化（皮质结构、细胞身份、形态学和连通性）。项目III将揭示CDSG中断的行为后果（听觉处理和学习），并将尝试通过行为干预来改善这些基因操作的影响。这三个互动项目将由一个行政核心、一个子宫内电穿孔核心和一个神经组织学、形态计量学和数据处理核心支持。更好地了解CDSGs的功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情况，同时也为早期发现、基于生物学的亚型和改进治疗提供了可能。

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.