Retrograde Signaling by Endogenous Cannabinoids

描述（由申请人提供）：大麻素，如d9-THC，影响 通过激活G-蛋白偶联的CB 1受体来抑制腺苷酸， 环化酶，调节多种离子通道，并抑制突触传递。 这些受体在整个大脑中广泛表达，特别是 在小脑皮层海马体中发现高水平的表达 和纹状体最近的研究提供了新的见解，以生理 大麻素系统的作用，并表明大麻素可以作为 逆行信使某些类型的树突中钙的升高 神经元导致磷脂的裂解，从而形成 释放内源性大麻素，其与突触前CB 1受体结合 来抑制突触传递这种逆行抑制持续数十年， 秒我们的主要目标是阐明这一特性和机制， 逆行抑制，并确定其生理作用。研究将 在啮齿动物小脑脑片上进行兴奋性和抑制性 已知被释放的大麻素逆向抑制的突触 来自浦肯野细胞树突这些突触非常适合这些研究 因为单元容易识别，所以整个单元电压钳位是直的 突触前和突触后的钙水平都可以被监测 光学上。机制研究将集中在钙依赖性， 大麻素释放，识别突触前靶点， 调制和决定其时间进程的因素。因素 控制着逆行抑制扩散到相邻突触 也将确定单元格及其空间范围。此外，我们将 确定逆行抑制的生理作用， 突触强度，并确定它是否是一种机制，可以提供 突触特异性调节，或者如果它提供了一个稳态机制， 细胞调节它接收的所有突触输入。这些基本 机械研究有望帮助大麻素实现其巨大的 作为食欲刺激剂、抗惊厥剂和 治疗亨廷顿病和帕金森病。

DESCRIPTION (provided by applicant): Cannabinoids, such as d9-THC, affect the brain by activating G-protein coupled CB1 receptors that can inhibit adenylate cyclase, modulate a variety of ion channels, and inhibit synaptic transmission. These receptors are expressed widely throughout the brain, with particularly high levels of expression found in the cerebellum, the cortex, the hippocampus and the striatum. Recent studies provide new insight into the physiological role of the cannabinoid system and suggest that cannabinoids can act as retrograde messengers. Elevations of calcium in the dendrites of some types of neurons result in the cleavage of phospholipids leading to the formation and liberation of endogenous cannabinoids, which bind to presynaptic CB1 receptors to inhibit synaptic transmission. This retrograde inhibition lasts for tens of seconds. Our primary goal is to clarify the properties and mechanisms of this retrograde inhibition and to determine its physiological role. Studies will be performed in rodent cerebellar brain slice on excitatory and inhibitory synapses that are known to be retrogradely inhibited by cannabinoids released from Purkinje cell dendrites. These synapses are well suited to these studies because cells are readily identified, whole cell voltage clamp is straight forward, and both presynaptic and postsynaptic calcium levels can be monitored optically. Mechanistic studies will concentrate on the calcium dependence of cannabinoid release, identification of the presynaptic targets of that modulation, and determination of the factors governing its time course. Factors governing the spread of retrograde inhibition to synapses onto neighboring cells and its spatial extent will also be determined. In addition, we will determine the physiological role of retrograde inhibition in controlling synaptic strength and determine if it is a mechanism that can provide synapse-specific regulation or if it provides a homeostatic mechanism for a cell to regulate all of the synaptic inputs it receives. These basic mechanistic studies promise to help cannabinoids realize their great therapeuptic potential as an appetite stimulant, as an anticonvulsant, and in the treatment of Huntington's disease and Parkinson's disease.