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: 7242587
• 负责人: CHARLES J FRAZIER
• 金额: $ 23.78万
• 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/7242587
• 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

DESCRIPTION (provided by applicant): 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 signaling 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.

描述（由申请人提供）：这是一项基础科学提案，旨在使用体外电生理学和光学技术来进一步了解负责调节肺门苔藓细胞突触输入活动的神经生理学机制。这些不寻常的兴奋性局部回路神经元从各种内在和外在来源接受强烈的谷氨酸能、GABA能和可能的胆碱能神经支配。苔藓细胞的正常功能被认为在海马的信息处理和记忆形成中发挥着重要作用，而它们的丧失和/或功能障碍与颞叶癫痫的病因有关。初步数据表明，苔藓细胞的抑制性和兴奋性输入活性均受到去极化诱导的内源性大麻素释放的调节。该提案的目标 1 将提供由苔藓细胞激活引发的大麻素依赖性信号传导的完整特征，并检查突触后胆碱能受体在调节内源性大麻素释放阈值中的作用。初步数据还表明，突触前 GABA 能受体在肺门苔藓细胞的一些兴奋性传入神经上表达，并进一步表明这些受体可能受到周围 GABA 的强直性抑制。因此，目标 2 将重点关注环境 GABA 作为这些兴奋性传入的潜在调节剂，并将最终确定内源性大麻素介导的逆行信号传导与抑制性音调之间是否存在有用的关系。最后，目标 3 将检验以下假设：长期接触天然和/或合成大麻素激动剂会损害该系统中内源性大麻素介导的逆行信号传导。这些实验可能揭示从根本上参与齿状回兴奋性、信息处理和记忆形成调节的特定神经生理学机制，并进一步确定它们在慢性药物滥用模型中如何随着时间的推移而改变。