Department of Molecular Pharmacology, Physiology and Biotechnology, Brown University, Providence, Rhode Island, USA.
Hippocampus. 2012 Feb;22(2):209-21. doi: 10.1002/hipo.20884. Epub 2010 Nov 10.
Endocannabinoids (eCBs) mediate various forms of synaptic plasticity at excitatory and inhibitory synapses in the brain. The eCB anandamide binds to several receptors including the transient receptor potential vanilloid 1 (TRPV1) and cannabinoid receptor 1 (CB1). We recently identified that TRPV1 is required for long-term depression at excitatory synapses on CA1 hippocampal stratum radiatum interneurons. Here we performed whole-cell patch clamp recordings from CA1 stratum radiatum interneurons in rat brain slices to investigate the effect of the eCB anandamide on excitatory synapses as well as the involvement of Group I metabotropic glutamate receptors (mGluRs), which have been reported to produce eCBs endogenously. Application of the nonhydrolysable anandamide analog R-methanandamide depressed excitatory transmission to CA1 stratum radiatum interneurons by ∼50%. The Group I mGluR agonist DHPG also depressed excitatory glutamatergic transmission onto interneurons to a similar degree, and this depression was blocked by the mGluR5 antagonist MPEP (10 μM) but not by the mGluR1 antagonist CPCCOEt (50 μM). Interestingly, however, neither DHPG-mediated nor R-methanandamide-mediated depression was blocked by the TRPV1 antagonist capsazepine (10 μM), the CB1 antagonist AM-251 (2 μM) or a combination of both, suggesting the presence of a novel eCB receptor or anandamide target at excitatory hippocampal synapses. DHPG also occluded R-methanandamide depression, suggesting the possibility that the two drugs elicit synaptic depression via a shared signaling mechanism. Collectively, this study illustrates a novel CB1/TRPV1-independent eCB pathway present in the hippocampus that mediates depression at excitatory synapses on CA1 stratum radiatum interneurons.
内源性大麻素（eCBs）在大脑中的兴奋性和抑制性突触处介导各种形式的突触可塑性。eCB 花生四烯酸乙醇酰胺与包括瞬时受体电位香草酸 1 型（TRPV1）和大麻素受体 1（CB1）在内的几种受体结合。我们最近发现 TRPV1 是 CA1 海马辐射状层中间神经元上兴奋性突触长时程抑制所必需的。在这里，我们在大鼠脑片的 CA1 辐射状层中间神经元上进行全细胞膜片钳记录，以研究内源性大麻素花生四烯酸乙醇酰胺对兴奋性突触的影响，以及涉及 I 组代谢型谷氨酸受体（mGluRs）的作用，据报道，I 组 mGluRs 可以产生内源性 eCBs。非水解型花生四烯酸乙醇酰胺类似物 R-甲硫氨酸乙醇酰胺的应用使 CA1 辐射状层中间神经元的兴奋性传递降低了约 50%。I 组 mGluR 激动剂 DHPG 也使兴奋性谷氨酸能传递到中间神经元的程度相似，这种抑制作用被 mGluR5 拮抗剂 MPEP（10 μM）阻断，但不受 mGluR1 拮抗剂 CPCCOEt（50 μM）阻断。然而，有趣的是，DHPG 介导的或 R-甲硫氨酸乙醇酰胺介导的抑制作用均不受 TRPV1 拮抗剂辣椒素（10 μM）、CB1 拮抗剂 AM-251（2 μM）或两者的联合阻断，这表明在兴奋性海马突触处存在一种新型的 eCB 受体或花生四烯酸乙醇酰胺靶标。DHPG 也阻断了 R-甲硫氨酸乙醇酰胺的抑制作用，这表明这两种药物可能通过共同的信号机制引起突触抑制。总的来说，这项研究说明了在海马体中存在一种新型的 CB1/TRPV1 独立的 eCB 途径，该途径介导 CA1 辐射状层中间神经元上兴奋性突触的抑制。
