Endocannabinoids and GABAergic Control of Plasticity

内源性大麻素和可塑性的 GABA 能控制

• 批准号: 8043604
• 负责人: BRADLEY E ALGER
• 金额: $ 27.95万
• 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 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8043604
• 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蛋白耦合，结合膜结合的受体的内源性激动剂，该受体对大麻中的活性成分响应，a9-四氢大麻酚。这些小脂质是细胞间神经信使，在哺乳动物中具有许多行为作用。内源性大麻素系统还参与了滥用药物的作用机理。在理解内源性大麻素的神经生理学方面的飞跃是，一些传统神经递质可以动员内源性大麻素的发现，从而激活了抑制性神经终端上的大麻素受体。大麻素受体的激活抑制了GABA释放。 I组代谢型谷氨酸受体（MGLURS）在减少GABA能抑制反应方面特别有效。如果维持几分钟，则MGlur启动的响应减少将变为永久性，并构成了抑制反应的长期抑郁症。内源性大麻素依赖性的，抑制性的长期抑郁症ECB-TILDD已经与抗恐惧条件反应的灭绝有关，在细胞水平上，促进了促进兴奋性突触的长期增强。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，但尚不清楚mglurs和ecb-tiltd的内源性大麻素生产的细胞机制的细节。该提案着重于海马中的mglur激活的内源性大麻素动员和欧洲央行。一个主要的假设是，这些反应受到高阶控制过程，即一种变性性的一种形式，可以调整（“素数”）mglurs与级联反应之间的耦合，最终在内源性大麻素释放和ECB-TILDD诱导中达到最终形式。该项目的具体目的是检验以下假设：1）内源性大麻素反应的增强是一种质外体性的一种形式； 2）增强是由一种新颖的启动机制引起的； 3）启动发生在内源性大麻素合成的上游； 4）启动涉及依赖钙的生化途径； 5）突触引起的ILTD受到启动。在整个神经系统中，MGLURS，GABA能突触和内源性大麻素在整个神经系统中都无处不在，在那里它们与许多生理和病理生理过程有关，包括学习和记忆，包括学习和记忆，癫痫，神经保护以及许多其他。本项目代表着一项集中努力，以填补我们对它们相互作用的理解。

项目成果

Novel mGluR- and CB1R-independent suppression of GABA release caused by a contaminant of the group I metabotropic glutamate receptor agonist, DHPG.

• DOI: 10.1371/journal.pone.0006122
• 发表时间: 2009-07-01
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Lafourcade CA;Zhang L;Alger BE
• 通讯作者: Alger BE

Reduction in endocannabinoid tone is a homeostatic mechanism for specific inhibitory synapses.

• DOI: 10.1038/nn.2517
• 发表时间: 2010-05
• 期刊: NATURE NEUROSCIENCE
• 影响因子: 25
• 作者: Kim, Jimok;Alger, Bradley E.
• 通讯作者: Alger, Bradley E.

Endocannabinoids generated by Ca2+ or by metabotropic glutamate receptors appear to arise from different pools of diacylglycerol lipase.

由 Ca2 或代谢型谷氨酸受体产生的内源性大麻素似乎来自不同的二酰基甘油脂肪酶池。

• DOI: 10.1371/journal.pone.0016305
• 发表时间: 2011
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Zhang,Longhua;Wang,Meina;Bisogno,Tiziana;DiMarzo,Vincenzo;Alger,BradleyE
• 通讯作者: Alger,BradleyE

Distinctions among GABAA and GABAB responses revealed by calcium channel antagonists, cannabinoids, opioids, and synaptic plasticity in rat hippocampus.

钙通道拮抗剂、大麻素、阿片类药物和大鼠海马突触可塑性揭示了 GABAA 和 GABAB 反应的区别。

• DOI: 10.1007/s00213-007-1040-4
• 发表时间: 2008
• 期刊: Psychopharmacology
• 影响因子: 3.4
• 作者: Lafourcade,CarlosA;Alger,BradleyE
• 通讯作者: Alger,BradleyE

Enhanced endocannabinoid signaling elevates neuronal excitability in fragile X syndrome.

• DOI: 10.1523/jneurosci.0795-10.2010
• 发表时间: 2010-04-21
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Zhang L;Alger BE
• 通讯作者: Alger BE