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，该受体对大麻中的活性成分A9-四氢大麻酚有反应。这些小脂质是哺乳动物中具有许多行为作用的细胞间神经信使。内源性大麻素系统也参与滥用药物的作用机制。随着一些传统的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，对内源性大麻素神经生理学的理解出现了飞跃。大麻素受体的激活抑制GABA的释放。I组代谢型谷氨酸受体（mGluR）在减少GABA能抑制反应中特别有效。如果维持几分钟，mGluR引发的反应降低变为永久性的，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）已经被证明与恐惧条件反应的消退有关，并在细胞水平上促进兴奋性突触的长时程增强。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信息处理，但mGluRs和eCB-iLTD产生内源性大麻素的细胞机制的细节尚不清楚。该提案的重点是mGluR激活的内源性大麻素动员和海马中的eCB-iLTD。一个主要的假设是，这些反应受到更高阶的控制过程，一种形式的超可塑性，调整（“启动”）mGluR和级联反应之间的耦合，最终在内源性大麻素释放和eCB-iLTD诱导。该项目的具体目的是测试以下假设：1）内源性大麻素反应的增强是一种形式的后可塑性; 2）增强是由一种新的引发机制引起的; 3）引发发生在内源性大麻素合成的上游; 4）引发涉及钙依赖性生化途径;和5）突触诱导的iLTD受到引发。MGluR、GABA能突触和内源性大麻素在整个神经系统中普遍存在，在神经系统中，它们单独参与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。目前的项目是一个集中的努力，以填补我们的理解他们的相互作用的关键差距。

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.