Retrograde Signaling by Endogenous Cannabinoids

描述(申请人提供)：大麻素，如D9-THC，会影响 激活G蛋白偶联CB1受体抑制腺苷酸化的脑 环化，调节各种离子通道，抑制突触传递。 这些受体在大脑中广泛表达，尤其是 在小脑、皮质、海马区高水平表达 还有纹状体。最近的研究为生理学提供了新的见解 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含量升高 神经元导致磷脂的裂解，导致形成和 与突触前CB1受体结合的内源性大麻素的释放 以抑制突触传递。这种逆行抑制持续了数十年 几秒钟。我们的主要目标是澄清这一现象的性质和机制 逆行抑制并确定其生理作用。研究将会是 在啮齿动物小脑脑片上进行兴奋和抑制 已知的被释放的大麻素逆行抑制的突触 来自浦肯野细胞的树突。这些突触非常适合这些研究。 因为电池很容易识别，所以整个电池电压钳是直的 向前，突触前和突触后的钙水平都可以监测 从光学上讲。机制研究将集中在钙依赖上。 大麻素释放，识别其突触前靶点 调制，并确定控制其时间进程的因素。因素 控制突触逆行抑制向邻近突触的扩散 单元格及其空间范围也将确定。此外，我们还将 确定逆行抑制在控制中的生理作用 突触强度并确定它是否是一种可以提供 突触特异性调节，或者如果它提供了一种动态平衡机制 细胞来调节它接收到的所有突触输入。这些基本 机械学研究有望帮助大麻类物质实现其伟大的 作为食欲刺激剂、抗惊厥药的治疗潜力，以及在 亨廷顿病和帕金森氏病的治疗。

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.