NEUROTRANSMITTER FUNCTION IN NEOCORTICAL NEUROGENESIS

描述（改编自申请人摘要）： 心理功能与细胞畸变有关， 大脑皮层 这些畸变的性质表明， 在神经元的发生和迁移过程中的发育早期。 所有 大脑皮层内的神经元在被禁止的区域内产生， 心室区（VZ），在整个离散和定义的时期。 是 越来越清楚的是，在VZ内起作用的信号调节着 皮质祖细胞的增殖和最终身份。 的 这里提出的实验将阐明细胞信号机制 在VZ内，由GABA和谷氨酸的激活介导 受体。 GABA和谷氨酸脱氢，增加细胞内钙 浓度，并减少分裂群体中DNA的合成 VZ内的细胞。 在这里描述的实验中， 膜片钳技术、钙离子成像和细胞周期动力学分析 将应用于体外外植体制备发育中的大脑 皮层，以进一步了解GABA和 谷氨酸调节皮层神经发生。 的具体目标 建议的实验是（1）识别电路中的发展 释放内源性GABA和谷氨酸激动剂的皮质， 调节VZ细胞的细胞周期，（2）指定GABA的作用， 谷氨酸对细胞周期动力学的影响，以及（3）确定是否增加 由GABA和谷氨酸启动的细胞内钙使细胞内钙离子 细胞周期的改变。 这些实验的结果将显示 新皮层神经元的发生受可扩散信号的调节 从发育中的大脑回路中释放出来

DESCRIPTION (Adapted from applicant's abstract): Several disorders in mental function have been correlated with cellular aberrations in the cerebral cortex. The nature of these aberrations indicates that they arise early in development during the genesis and migration of neurons. All neurons within the cerebral cortex are generated within a proscribed region, the ventricular zone (VZ), throughout a discrete and defined period. It is becoming increasingly clear that signals acting within the VZ regulate both the proliferation and ultimate identity of cortical progenitors. The experiments proposed here will elucidate cellular signaling mechanisms within the VZ that are mediated by activation of GABA and glutamate receptors. GABA and glutamate depolarize, increase intracellular calcium concentration, and decrease the synthesis of DNA in the dividing population of cells within the VZ. In the experiments described here, a combination of patch-clamp techniques, calcium imaging, and assays of cell cycle kinetics will be applied to an in vitro explant preparation of developing cerebral cortex in order to further understand the mechanisms by which GABA and glutamate regulate cortical neurogenesis. The specific objectives of the proposed experiments are to (1) identify the circuits in the developing cortex that release the endogenous GABA and glutamate agonists which regulate the cell cycle of VZ cells, (2) specify effects of GABA and glutamate on cell cycle kinetics, and (3) determine whether the rise in intracellular calcium initiated by GABA and glutamate subserves the alterations in cell cycle. The results from these experiments will show how the genesis of neurons in the neocortex is regulated by diffusible signals released from circuits within the developing brain.