NEUROGENESIS IN DISORDERS OF BRAIN DEVELOPMENT

描述(改编自申请人的摘要)：精神疾病的原因 唐氏综合征(DS)的发育迟缓尚不清楚，但被认为是导致的， 至少部分是由于胚胎时期大脑发育缺陷所致。 当大脑皮层的神经元正在生成时。16三体(TS16) 小鼠与DS有共同的遗传缺陷，可能有助于研究 大脑皮层胚胎发育异常的机制。 TS16小鼠大脑皮质有丝分裂后神经元的出生前发育延迟 而板下神经元与皮质板神经元同时出生。 而不是像在正常皮质中那样在它们之前。这些时间上的异常 TS16神经发生的缺失可能导致成熟脑中的连接缺陷； 在人脑的产前发育过程中，类似的缺陷可能 导致精神发育迟滞的DS。 神经前体细胞(神经母细胞)的增殖及其决定 子细胞离开细胞周期，这最终控制着 神经发生受神经递质和生长因子的调节，如 谷氨酸和脑源性神经营养因子(BDNF)。TS16神经母细胞失败 对谷氨酸和BDNF做出反应，增加了这种信号传递的可能性 缺陷可能是TS16神经发生延迟的原因。 TS16神经发生调控缺陷的分子基础将是 在a)分离的神经母细胞培养和b)器官型中研究 取自TS16和斜生整倍体皮质的切片。这两种准备工作 不仅能够直接应用假定的神经发生调节因子 以及信号通路的抑制物，但也直接测量 细胞增殖、细胞死亡和细胞内钙离子水平--钙离子的关键调节因子 增殖、神经元分化和迁移。实验在 器官类型切片将使这些过程能够在结构上进行分析 完整的大脑皮层，将允许解剖上不同的种群的行为 神经母细胞和有丝分裂后神经元的区别。 本研究项目的总体目标是确定信令 导致TS16小鼠大脑皮层异常神经发生的缺陷 同时，确定分子信号转导机制 以控制正常大脑中的神经发生为基础。

DESCRIPTION (adapted from applicant's abstract): The cause of mental retardation in Down syndrome (DS) is not understood but is thought to result, at least in part, from defective brain development during the embryonic period when neurons of the cerebral cortex are being generated. The trisomy 16 (Ts16) mouse shares a common genetic defect with DS and may be useful for studying the mechanisms underlying abnormal embryonic development of the cerebral cortex. Prenatal generation of postmitotic neurons in the Ts16 mouse cortex is delayed and subplate neurons are born concurrently with cortical plate neurons rather than preceding them as in the normal cortex. These abnormalities in the timing of Ts16 neurogenesis may lead to defective connectivity in the mature brain; similar defects during the prenatal development of the human brain may contribute to mental retardation in DS. Proliferation of neuroprogenitor cells (neuroblasts) and the decision of daughter cells to leave the cell cycle, which ultimately control the timing of neurogenesis, are regulated by neurotransmitters and growth factors such as glutamate and brain derived neurotrophic factor (BDNF). Ts16 neuroblasts fail to respond to glutamate and BDNF, raising the possibility that this signaling defect may underlie delayed neurogenesis in Ts16. The molecular basis for defects in the regulation of Ts16 neurogenesis will be studied in a) dissociated cell cultures of neuroblasts and b) organotypic slices from Ts16 and littermate euploid cortex. Both of these preparations enable not only the direct application of putative regulators of neurogenesis and of inhibitors of signaling pathways, but also direct measurement of proliferation, cell death and intracellular levels of Ca2+, a key modulator of proliferation, neuronal differentiation and migration. Experiments in organotypic slices will enable these processes to be analyzed in a structurally intact cortex and will allow the behavior of anatomically-distinct populations of neuroblasts and postmitotic neurons to be distinguished. The overall goals of this research project are to identify the signaling defects that lead to abnormal neurogenesis in the Ts16 mouse cerebral cortex and, at the same time, to determine the molecular signaling mechanisms underlying the control of neurogenesis in the normal brain.