The transient receptor potential vanilloid 1 (TRPV1) is a non-selective ligand-gated cationic channel involved in synaptic transmission, plasticity and brain pathology. In the hippocampal dentate gyrus, TRPV1 localizes to dendritic spines and dendrites postsynaptic to excitatory synapses in the molecular layer (ML). At these same synapses, the cannabinoid CB1 receptor (CB1R) activated by exogenous and endogenous cannabinoids localizes to the presynaptic terminals. Hence, as both receptors are activated by endogenous anandamide, co-localize and mediate long-term depression of the excitatory synaptic transmission at the medial perforant path (MPP) excitatory synapses though by different mechanisms, it is likely that they might be having an effect on each other from their opposite synaptic sites. In this study, we tested whether the absence of TRPV1 affects the endocannabinoid system. The results obtained using biochemical techniques and immunoelectron microscopy in a mouse model with the genetic deletion of TRPV1 show that the expression and localization of components of the endocannabinoid system, included CB1R, change upon the constitutive absence of TRPV1. Thus, the expression of fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) drastically increased in TRPV1-/- whole homogenates. Furthermore, CB1R and MAGL decreased and the cannabinoid receptor interacting protein 1a (CRIP1a) increased in TRPV1-/- synaptosomes. In TRPV1-/- dentate ML, the excitatory terminals were less numerous and enlarged but the percentage of CB1R positive excitatory terminals was augmented. In the inner 1/3 ML, the proportion of CB1R particles significantly dropped in inhibitory terminals but raised significantly in excitatory terminals, neuronal mitochondria and dendrites. Particle distribution in inhibitory and excitatory terminals, mitochondria and astrocytes was not altered significantly in the outer 2/3 ML of TRPV1-/-. Altogether, these observations indicate the existence of compensatory changes in the endocannabinoid system upon TRPV1 removal, and endorse the importance of the potential functional adaptations derived from the lack of TRPV1 in the mouse brain.

中文翻译：

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瞬态受体电位香草醛1的缺乏直接影响小鼠海马内源性大麻素系统的表达和定位。

瞬时受体电位香草酸1（TRPV1）是一种非选择性配体门控的阳离子通道，参与突触传递，可塑性和脑部病理学。在海马齿状回中，TRPV1定位于树突棘，而突触后树突则位于分子层（ML）的兴奋性突触中。在这些相同的突触中，由外源性和内源性大麻素激活的大麻素CB1受体（CB1R）定位于突触前末端。因此，尽管这两种受体均被内源性阿南酰胺激活，但通过不同的机制，共同定位并介导了内侧穿孔路径（MPP）兴奋性突触的兴奋性突触传递的长期抑制，所以它们可能具有一定的作用。彼此相对的突触位点 在这项研究中，我们测试了TRPV1的缺失是否会影响内源性大麻素系统。使用生化技术和免疫电子显微镜在具有TRPV1基因缺失的小鼠模型中获得的结果表明，内含大麻素系统的成分（包括CB1R）的表达和定位在组成性缺失TRPV1时发生变化。因此，在TRPV1-/-全匀浆中，脂肪酸酰胺水解酶（FAAH）和单酰基甘油脂酶（MAGL）的表达急剧增加。此外，TRPV1-/-突触小体中的CB1R和MAGL降低，大麻素受体相互作用蛋白1a（CRIP1a）增加。在TRPV1-/-齿状ML中，兴奋性末端较少并且扩大，但是CB1R阳性兴奋性末端的百分比增加。在内部1/3 ML中，CB1R颗粒的比例在抑制性末端显着下降，而在兴奋性末端，神经元线粒体和树突中则显着上升。TRPV1-/-的外部2/3 ML中，抑制性和兴奋性末端，线粒体和星形胶质细胞中的颗粒分布没有明显改变。总而言之，这些观察结果表明，去除TRPV1后内源性大麻素系统存在代偿性变化，并认可了由于小鼠脑内TRPV1缺乏而引起的潜在功能适应性的重要性。