Endocannabinoids and GABAergic Control of Plasticity

描述(由申请人提供)：内源性大麻素是G蛋白偶联的膜结合受体的内源性激动剂，它对大麻中的活性成分A9-四氢大麻酚做出反应。这些小脂质是哺乳动物细胞间的神经信使，在哺乳动物中扮演着许多行为角色。内源性大麻素系统也参与滥用药物的作用机制。随着一些常规神经递质可以动员内源性大麻素，从而激活抑制神经末梢上的大麻素受体，人们在理解内源性大麻素的神经生理学方面取得了飞跃。大麻素受体的激活抑制了GABA的释放。I类代谢性谷氨酸受体(MGluRs)在减少GABA能抑制反应方面特别有效。如果维持几分钟，mGluR启动的反应减少将成为永久性的，并构成抑制反应的长期抑制。依赖内源性大麻素的抑制性长期抑郁，ECB-iLTD，已经被认为与抵抗恐惧条件性反应的消退有关，并且在细胞水平上，在促进兴奋性突触的长期增强方面也被涉及。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以深刻的方式影响神经元的信息处理，但mGluRs和ECB-iLTD产生内源性大麻素的细胞机制尚不清楚。这项建议的重点是mGluR激活的内源性大麻素动员和ECB-iLTD在海马区。一个主要的假设是，这些反应受到更高级别的控制过程，这是一种变塑性的形式，调节(“素数”)mGluRs和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。该项目的具体目的是检验以下假设：1)内源性大麻反应的增强是一种化塑性；2)这种增强是由一种新的启动机制引起的；3)启动发生在内源性大麻素合成的上游；4)启动涉及钙依赖的生化途径；以及5)突触诱导的iLTD受到启动的影响。MGluRs、GABA能突触和内源性大麻素在神经系统中普遍存在，它们分别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。本项目是一项有重点的努力，以填补我们在了解它们之间的相互作用方面的重大空白。

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.