Endocannabinoids and tonic GABA in the dentate gyrus.

齿状回中的内源性大麻素和补品 GABA。

• 批准号: 7473458
• 负责人: CHARLES J FRAZIER
• 金额: $ 4.03万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-15 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7473458
• 关键词: Acids; Address; Affinity; Agonist; Area; Basic Science; Bathing; Behavioral; Calcium; Cannabinoids; Cells; Cholinergic Agents; Cholinergic Receptors; Chromosome Pairing; Chronic; Class; Computer information processing; Data; Dependence; Drug abuse; Endocannabinoids; Etiology; Exposure to; Functional disorder; Glutamates; Goals; Hilar; Hippocampus (Brain); In Vitro; Lead; Learning; Marijuana Abuse; Mediating; Memory; Modeling; Muscarinic Acetylcholine Receptor; Muscarinic Agonists; Neurons; Optics; Play; Preparation; Presynaptic Terminals; Rattus; Regulation; Research Personnel; Role; Signal Transduction; Source; Specificity; Synapses; System; Techniques; Temporal Lobe Epilepsy; Testing; Time; Work; base; cannabinoid receptor; cholinergic; dentate gyrus; design; gamma-Aminobutyric Acid; insight; memory process; nerve supply; neurophysiology; postsynaptic; presynaptic; programs; receptor; research study

This is a basic science proposal designed to use in vitro electrophysiological and optical techniques to further our understanding of the neurophysiological mechanisms responsible for modulating the activity of synaptic inputs to hilar mossy cells. These unusual excitatory local circuit neurons receive strong glutamatergic, GABAergic, and likely cholinergic innervation from a variety of intrinsic and extrinsic sources. Normal function of mossy cells has been postulated to play a prominent role in information processing and memory formation in the hippocampus, while their loss and/or dysfunction has been implicated in the etiology of temporal lobe epilepsy. Preliminary data indicate that the activity of both inhibitory and excitatory inputs to mossy cells is modulated by depolarization-induced release of endogenous cannabinoids. Aim 1 of this proposal will provide a complete characterization of cannabinoid dependent signaling initiated by activation of mossy cells, and examine the role of postsynaptic cholinergic receptors in modulating the threshold for endocannabinoid release. Preliminary data has also indicated that presynaptic GABAergic receptors are expressed on some excitatory afferents to hilar mossy cells and further suggested that these receptors are likely subject to tonic inhibition by ambient GABA. Thus, Aim 2 will focus on ambient GABA as a potential modulator of these excitatory afferents and will ultimately determine if there is a useful relationship between endocannabinoid mediated retrograde signaling and inhibitory tone. Finally, Aim 3 will test the hypothesis that endocannabinoid mediated retrograde signalling in this system is impaired by chronic exposure to natural and/or synthetic cannabinoid agonists. These experiments may expose specific neurophysiological mechanisms that are fundamentally involved in regulation of excitability, information processing, and memory formation in the dentate gyrus, and further determine how they are altered over time in a chronic model of drug abuse.

这是一项基础科学建议，旨在将体外电生理学和光学技术用于 进一步，我们对负责调节活性的神经生理机制的理解 肺苔藓细胞的突触输入。这些不寻常的兴奋性局部电路神经元获得强大 谷氨酸能，GABA能和可能来自各种固有和外在的胆碱能神经 来源。已经假定苔藓细胞的正常功能在信息中发挥着重要作用 海马中的处理和记忆形成，而它们的损失和/或功能障碍已 与颞叶癫痫的病因有关。初步数据表明两者的活动 通过去极化诱导的释放来调节对苔藓细胞的抑制和兴奋性输入 内源性大麻素。该提案的目标1将提供大麻素的完整特征 通过激活苔藓细胞引发的依赖信号传导，并检查突触后胆碱能的作用 调节内源性大麻素释放的阈值时的受体。初步数据也已指出 突触前的GABA能受体在某些兴奋性传入中表达了hilar苔藓细胞和 进一步表明，这些受体可能会受到环境GABA的滋补抑制作用。因此，目标2 将专注于环境GABA作为这些兴奋性传入的潜在调节器，并最终将 确定内源性大麻素介导的逆行信号和 抑制语调。最后，AIM 3将测试内源性大麻素介导的逆行信号的假设 在该系统中，长期暴露于天然和/或合成大麻素激动剂会受到损害。这些 实验可能会揭示从根本上涉及的特定神经生理机制 调节齿状回的兴奋性，信息处理和记忆形成，并进一步调节 在慢性药物滥用模型中确定它们如何随着时间的流逝而改变。