Endocannabinoids and GABAergic Control of Plasticity

内源性大麻素和可塑性的 GABA 能控制

• 批准号: 7600562
• 负责人: BRADLEY E ALGER
• 金额: $ 29.11万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-30 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7600562
• 关键词: Agonist; Behavioral; Biochemical Pathway; Brain; Calcium; Cannabis; Coupled; Coupling; Endocannabinoids; Epilepsy; Excitatory Synapse; Extinction (Psychology); Fostering; GTP-Binding Proteins; Hippocampus (Brain); Human; Learning; Lipids; Long-Term Depression; Long-Term Potentiation; Mammals; Membrane; Memory; Metabotropic Glutamate Receptors; Nerve; Nervous system structure; Neurons; Neurotransmitters; Physiological; Physiological Processes; Process; Production; Reaction; Resistance; Role; Synapses; System; Testing; Tetrahydrocannabinol; cannabinoid receptor; conditioned fear; drug of abuse; gamma-Aminobutyric Acid; information processing; neurophysiology; neuroprotection; novel; receptor; receptor binding; relating to nervous system; response

DESCRIPTION (provided by applicant): Endocannabinoids are the endogenous agonists for the G-protein coupled, membrane-bound receptor that responds to the active ingredient in cannabis, A9-tetrahydrocannabinol. These small lipids are intercellular neural messengers with numerous behavioral roles in mammals. Endocannabinoid systems are also involved in the mechanisms of action of abused drugs. A leap forward in understanding the neurophysiology of endocannabinoids came with the discovery that some conventional neurotransmitters can mobilize endocannabinoids, thereby activating cannabinoid receptors on inhibitory nerve terminals. Activation of cannabinoid receptors inhibits GABA release. The group I metabotropic glutamate receptors (mGluRs) are especially effective in reducing GABAergic inhibitory responses. If maintained for a few minutes, the mGluR- initiated response reduction becomes permanent and constitutes a long-term depression of the inhibitory responses. Endocannabinoid-dependent, inhibitory long-term depression, eCB-iLTD, has already been implicated in resistance to extinction of fear-conditioned responses, and at the cellular level, in fostering long-term potentiation of excitatory synapses. The widespread distribution of endocannabinoids and their receptors in the brain enable endocannabinoids to influence neuronal information processing in profound ways, yet details of the cellular mechanisms of endocannabinoid production by mGluRs and eCB-iLTD are not understood. This proposal focuses on mGluR-activated endocannabinoid mobilization and eCB-iLTD in the hippocampus. A major hypothesis is that these responses are subject to a higher order control process, a form of metaplasticity, that adjusts ("primes") the coupling between mGluRs and the cascade of reactions culminating in endocannabinoid release and eCB-iLTD induction. The specific aims of the project are to test the hypotheses that: 1) enhancement of endocannabinoid responses is a form of metaplasticity; 2) the enhancement is caused by a novel priming mechanism; 3) priming occurs upstream of endocannabinoid synthesis; 4) priming involves calcium-dependent biochemical pathways; and 5) that synaptically-induced iLTD is subject to priming. MGluRs, GABAergic synapses, and endocannabinoids are ubiquitous throughout the nervous system, where they have individually been implicated in a host of physiological and pathophysiological processes, including learning and memory, epilepsy, neuroprotection, and many others. The present project represents a focused effort to fill in critical gaps in our understanding of their interactions.

描述（由申请人提供）：内源性大麻素是 G 蛋白偶联膜结合受体的内源性激动剂，可响应大麻中的活性成分 A9-四氢大麻酚。这些小脂质是细胞间神经信使，在哺乳动物中具有多种行为作用。内源性大麻素系统也参与滥用药物的作用机制。随着一些传统神经递质可以动员内源性大麻素，从而激活抑制性神经末梢上的大麻素受体的发现，对内源性大麻素的神经生理学的理解发生了飞跃。大麻素受体的激活会抑制 GABA 的释放。 I 类代谢型谷氨酸受体 (mGluR) 在减少 GABA 能抑制反应方面特别有效。如果维持几分钟，mGluR 引发的反应减少将变成永久性的，并构成抑制反应的长期抑制。内源性大麻素依赖性抑制性长期抑郁症（eCB-iLTD）已被证明与抵抗恐惧条件反应的消退有关，并且在细胞水平上与促进兴奋性突触的长期增强有关。内源性大麻素及其受体在大脑中的广泛分布使内源性大麻素能够深刻地影响神经元信息处理，但 mGluR 和 eCB-iLTD 产生内源性大麻素的细胞机制的细节尚不清楚。该提案重点关注海马中 mGluR 激活的内源性大麻素动员和 eCB-iLTD。一个主要假设是，这些反应受到更高阶的控制过程（一种化塑性形式）的影响，该过程调整（“引发”）mGluR 与最终导致内源性大麻素释放和 eCB-iLTD 诱导的级联反应之间的耦合。该项目的具体目标是测试以下假设：1）内源性大麻素反应的增强是一种化塑性形式； 2）这种增强是由一种新颖的启动机制引起的； 3) 引发发生在内源性大麻素合成的上游； 4）启动涉及钙依赖性生化途径； 5) 突触诱导的 iLTD 受到启动作用。 MGluR、GABA能突触和内源性大麻素在整个神经系统中无处不在，它们各自参与了许多生理和病理生理过程，包括学习和记忆、癫痫、神经保护等。当前的项目代表了我们为填补我们对它们相互作用的理解中的关键空白而做出的集中努力。