Retrograde Signaling by Endogenous Cannabinoids

描述（由申请人提供）：最近发现神经元可以从其细胞体和树突释放内源性大麻素（eCBs）来激活突触前1型大麻素受体（CB1Rs）。尽管进行了深入研究，但有关欧洲央行信号的许多基本问题仍未得到解答。研究表明，脑电刺激可以短暂地降低神经递质释放的概率，但这种短期可塑性的生理作用是什么？释放eCB是否允许细胞在生理条件下对其所有突触进行全局调节？eCB信号是否提供了短期联合突触可塑性的一般机制？eCB释放是否专门针对不同的细胞类型来调节联想可塑性的时间和频率依赖性？ecb是否允许突触的目标依赖性调节？欧洲央行的信号是如何调制的？先前的研究也表明，突触前CB1Rs控制小脑突触后长期抑郁（LTD）的诱导，这在运动学习中起着重要作用。cb1r如何控制这种有限公司形式？eCB释放的性质是否导致了适合于运动学习的LTD诱导的时间依赖？eCB也可以调节某些类型细胞的兴奋性，尽管这方面的eCB信号传导比突触调节研究得少得多。是ecb调节整个大脑细胞的神经元兴奋性，还是这是一种罕见的信号形式？为什么一些细胞能调节自己的兴奋性，而另一些细胞只受到邻近细胞释放的ecb的影响？为什么电刺激会导致某些细胞类型的兴奋性持续变化，而对其他细胞类型的影响只是短暂的？

DESCRIPTION (provided by applicant): It was recently discovered that neurons can release endocannabinoids (eCBs) from their cell bodies and dendrites to activate presynaptic type 1 cannabinoid receptors (CB1Rs). Despite intensive study many fundamental questions about eCB signaling remain unanswered. It has been shown that eCBs can transiently decrease the probability of neurotransmitter release, but what is the physiological role of such short term plasticity? Does eCB release allow cells to globally regulate all of their synapses under physiological conditions? Does eCB signaling provide a general mechanism for short-term associative synaptic plasticity? Is eCB release specialized in different cell types to regulate the timing and frequency dependence of associative plasticity? Do eCBs allow target-dependent regulation of synapses? How is eCB signaling modulated? Previous studies have also shown that presynaptic CB1Rs control the induction of a postsynaptic form of long-term depression (LTD) in the cerebellum that plays an important role in motor learning. How do CB1Rs control this form of LTD? Do the properties of eCB release lead to a timing dependence for the induction of LTD that is suited to motor learning? eCBs can also regulate the excitability of some types of cells, although this aspect of eCB signaling is much less studied than synaptic regulation. Do eCBs regulate neuronal excitability for cells throughout the brain or is this a rare form of signaling? Why do eCBs allow some cells to regulate their own excitability whereas others are only influenced by eCBs released from neighboring cells? Why do eCBs lead to sustained changes in excitability in some cell types and only transiently affect others? These questions will be addressed by studying eCB signaling in brain slices from rats and mice. Studies will use whole-cell voltage clamp and current-clamp recordings to evoke eCB release, quantify changes in synaptic strength, monitor firing properties and measure effects on membrane potential. Postsynaptic calcium, which is a vital regulator of eCB release, will be measured and manipulated. Quantification of presynaptic calcium entry, which is regulated by CB1R activation, will provide a measure of eCB-mediated presynpatic modulation and will allow us to study individual presynaptic cells. Virtually all of the techniques required in this study are routinely used in the laboratory, making it likely that the proposed experiments will be completed in the allocated time. These studies will lead to a deeper understanding of the role of eCB signalling in the cerebellum, motor control and motor learning. They will also provide general insight into eCB signaling that will aid in the understanding of pain, epilepsy, appetite control, depression and Parkinson's disease.