Role of L-Type Calcium Channels in Hippocampal Neuronal Network Activity

L 型钙通道在海马神经元网络活动中的作用

• 批准号: 7669376
• 负责人: Scott Owen
• 金额: $ 3.22万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7669376
• 关键词: Acute; Affect; Agonist; Animal Model; Brain; Cell physiology; Disease; Disease model; Equilibrium; Genes; Genetic; Goals; Hippocampus (Brain); Investigation; L-Type Calcium Channels; Link; Mental disorders; Modeling; Molecular; Mutation; Neurons; Nucleotides; Pattern; Physiological Processes; Preparation; Rattus; Role; Series; Slice; Synapses; Synaptic Transmission; System; Testing; Timothy syndrome; autism spectrum disorder; base; disease phenotype; nervous system disorder; neural circuit; novel; postsynaptic; public health relevance; research study

DESCRIPTION (provided by applicant): Autism spectrum disorder (ASD) is a pervasive but poorly understood neurological disorder. Timothy Syndrome, a disorder with a highly significant link to ASD, has recently been shown to have a monogenetic origin in a single nucleotide substitution within the L-type Ca2+ channel. This mutation prolongs channel opening, an effect that can be mimicked pharmacologically by the L-type Ca2+ channel agonist BayK 8644. In this way we can recapitulate TS in an animal model to generate findings that can potentially generalize to other ASDs. This animal model allows for a detailed investigation of TS from molecular mechanisms to hippocampal circuitry. The goal of this proposal is to characterize the effects of BayK 8644 on physiological processes in the hippocampus at multiple levels from synapses to circuits and to provide a roadmap for how a single molecular malfunction can affect the functioning of a neural circuit leading to a disease phenotype.l. Specific Aim 1 - To test the hypothesis that BayK 8644 leads to enhanced activation of a postsynaptic Ca2+-activated K+ conductances during excitatory synaptic transmission. We have demonstrated that BayK 8644 has a dampening effect on excitatory synaptic transmission in acute slices of rat hippocampus. We propose a series of experiments to characterize the cellular physiology underlying this surprising effect. II. Specific Aim 2 - To develop a system for studying behaviorally relevant network dynamics in a hippocampal slice preparation. We have developed a novel system using multi-unit tetrode recordings to study pattern separation in an acute hippocampal slice. Using this well-controlled slice preparation, we propose to probe the network transition point between pattern completion and pattern separation. III. Specific Aim 3 - To test the hypothesis that BayK 8644 interferes with hippocampal circuit dynamics by upsetting the balance of excitatory and inhibitory influences in the circuit. By applying BayK 8644 during a series of experiments similar to those described in Aim 2, we propose to test how the behaviorally relevant circuit dynamics are affected in an acute model of autism spectrum disorder. We will combine intracellular and tetrode recordings in order to connect the subcellular to the macroscopic effects of this disease model. PUBLIC HEALTH RELEVANCE: Autism spectrum disorder is a common and profoundly debilitating psychological disorder. While recent evidence has implied a genetic basis for this disease, we know very little about how to connect genes to function to [eventually] treatment. We propose here a series of experiments to develop a deeper understanding of how one model of autism spectrum disorder might function at multiple levels from genes to molecules to neural circuits as they function in the brain.

描述（由申请人提供）：自闭症谱系障碍（ASD）是一种普遍但知之甚少的神经系统疾病。蒂莫西综合征是一种与ASD有着显着联系的疾病，最近已被证明在L型Ca2+通道内的单个核苷酸取代中具有单基因的起源。该突变延长了通道的开口，可以通过L型Ca2+通道激动剂Bayk 8644在药理学上模仿这种效果。通过这种方式，我们可以在动物模型中概括TS，以产生可能概括到其他ASDS的发现。该动物模型允许对从分子机制到海马电路的TS进行详细研究。该提案的目的是表征Bayk 8644对从突触到电路的多个级别的海马生理过程的影响，并为单个分子故障如何影响导致疾病表型的神经回路的功能提供路线图。特定目的1-测试Bayk 8644导致突触后激活增强的假设 兴奋性突触传播过程中Ca2+激活的K+电导。我们已经证明了Bayk 8644对大鼠海马急性切片中的兴奋性突触传播具有减弱作用。我们提出了一系列实验，以表征这种令人惊讶作用的细胞生理。 ii。特定目标2-开发用于研究海马切片制备中与行为相关的网络动态的系统。我们已经开发了一种使用多单位四极记录的新型系统来研究急性海马切片中的模式分离。使用这种控制良好的切片准备，我们建议在模式完成和模式分离之间探测网络过渡点。 iii。特定目的3-测试Bayk 8644通过破坏电路中兴奋性和抑制性影响的平衡而干扰海马电路动力学的假设。通过在类似于AIM 2中所述的一系列实验中应用Bayk 8644，我们建议在自闭症谱系障碍的急性模型中测试与行为相关的电路动力学的影响。我们将结合细胞内和四极的记录，以将亚细胞与该疾病模型的宏观效应联系起来。公共卫生相关性：自闭症谱系障碍是一种常见且令人衰弱的心理障碍。尽管最近的证据暗示了该疾病的遗传基础，但我们对如何将基因连接到[最终]治疗方面知之甚少。我们在这里提出了一系列实验，以更深入地了解一种自闭症谱系障碍模型如何在从基因到分子到神经回路的多个级别起作用，因为它们在大脑中起作用。