DEVELOPMENT/MODULATION OF CALCIUM CURRENTS IN NEOCORTEX

描述：（申请人摘要） 新皮层锥体神经元是研究其机制的模型系统 以及突触传入信号转导为锋电位序列的意义。几 该转导过程的各个方面是Ca 2+依赖性的，包括调节 锋电位间期（ISI）、锋电位频率适应（SFA）、锋电位 定时和后超极化（AHPs）。锥体细胞至少表达 五种不同的高电压激活的钙离子通道我们假设Ca 2 + 进入对这些细胞有不同的后果，这取决于哪些钙 涉及通道子类型。这种功能划分的一个例子是 生成AHP：N、P和Q型通道耦合到sAHP和P型通道， 到mAHP。两个控制Ca ~（2+）进入的关键负反馈系统是 Ca 2+依赖性的Ca 2+通道失活和Ca 2+依赖性的Ca 2+通道激活 K+通道。这两个过程都是锥体细胞放电的潜在调节器 行为我们将使用全细胞电记录和fura-2 Ca 2+成像 急性分离和脑内成熟锥体细胞的技术 切片制备，以测试关于Ca 2+依赖性 失活以及动作电位、[Ca 2 +]i和AHP之间的关系 电流（由于Ca 2+依赖性K+通道）。目标1强调以下方面的重要性： Ca 2+依赖性失活的Ca 2+通道亚型和哪些通道亚型 参与其中目标2描述了放电频率， 成熟锥体细胞内[Ca ~（2+）]i。这些数据对于 了解锥体细胞如何整合突触输入， 这一过程受递质和个体发育的影响。(In新皮质锥体 神经元，Ca 2+和Ca 2 +-dep K+通道都受到发育调节， 是几种神经调质的靶点）。神经元活动及其调节 调节皮质功能和皮质的使用依赖性可塑性 连接.这些研究将有助于理解大脑皮层的基本功能 注意力、学习和记忆等功能以及基本机制 癫痫、焦虑和抑郁症等疾病。

DESCRIPTION: (Applicant's Abstract) Neocortical pyramidal neurons are a model system for study of the mechanisms and significance of transduction of synaptic inputs into spike trains. Several aspects of this transduction process are Ca2+-dependent, including regulation of the interspike interval (ISI), spike frequency adaptation (SFA), spike timing and afterhyperpolarizations (AHPs). Pyramidal cells express at least five different high voltage-activated Ca2+ channels. We hypothesize that Ca2+ entry has different consequences for these cells, depending upon which calcium channel subtypes are involved. An example of such partitioning of function is generation of AHPs: N-, P-, and Q-type channels couple to the sAHP and P-type to the mAHP. Two critical negative feedback systems controlling Ca2+ entry are Ca2+-dependent inactivation of Ca2+ channels and activation of Ca2+-dependent K+ channels. Both processes are potential regulators of pyramidal cell firing behavior. We will use whole cell electrical recordings and fura-2 Ca2+ imaging techniques on mature pyramidal cells in both acutely dissociated and brain slice preparations to test hypotheses about the roles of Ca2+-dependent inactivation and the relationships between action potentials, [Ca2+]i, and AHP currents (due to Ca2+-dependent K+ channels). Aim 1 addresses the importance of Ca2+-dependent inactivation of Ca2+ channel subtypes and which channel subtypes are involved. Aim 2 characterizes the relationships between firing frequency, IAHP, and [Ca2+]i in mature pyramidal cells. These data are important for understanding how pyramidal cells integrate synaptic inputs, and how this process is influenced by transmitters and ontogeny. (In neocortical pyramidal neurons, both Ca2+ and Ca2+-dep K+ channels are developmentally regulated and are targets for several neuromodulators). Neuronal activity and its modulation regulate cortical function and the use-dependent plasticity of cortical connections. These studies will contribute to understanding essential cortical functions such as attention, learning, and memory as well as basic mechanisms of diseases such as epilepsy, anxiety and depression.