INMED, INSERM U901, 13273 Marseille , France.
Aix-Marseille University , 13007 Marseille , France.
ACS Chem Neurosci. 2018 Sep 19;9(9):2233-2240. doi: 10.1021/acschemneuro.7b00398. Epub 2018 Mar 8.
We investigated how metabotropic acetylcholine receptors control excitatory synaptic plasticity in the mouse nucleus accumbens core. Pharmacological and genetic approaches revealed that M mAChRs (muscarinic acetylcholine receptors) trigger multiple and interacting forms of synaptic plasticity. As previously described in the dorsal striatum, moderate pharmacological activation of M mAChR potentiated postsynaptic NMDARs. The M-potentiation of NMDAR masked a previously unknown coincident TRPV1-mediated long-term depression (LTD). In addition, strong pharmacological activation of M mAChR induced canonical retrograde LTD, mediated by presynaptic CB1R. In the fmr1-/y mouse model of Fragile X, we found that CB1R but not TRPV1 M-LTD was impaired. Finally, pharmacological blockade of the degradation of anandamide and 2-arachidonylglycerol, the two principal endocannabinoids restored fmr1-/y LTD to wild-type levels. These findings shed new light on the complex influence of acetylcholine on excitatory synapses in the nucleus accumbens core and identify new substrates of the synaptic deficits of Fragile X.
我们研究了代谢型乙酰胆碱受体如何控制小鼠伏隔核核心中的兴奋性突触可塑性。药理学和遗传学方法表明，M mAChR（毒蕈碱乙酰胆碱受体）触发多种相互作用的突触可塑性形式。如以前在背侧纹状体中所描述的，M mAChR 的适度药理学激活增强了突触后 NMDAR。M 增强作用掩盖了先前未知的伴随 TRPV1 介导的长时程抑制（LTD）。此外，M mAChR 的强烈药理学激活诱导由突触前 CB1R 介导的经典逆行 LTD。在脆性 X 综合征的 fmr1-/y 小鼠模型中，我们发现 CB1R 而不是 TRPV1 M-LTD 受损。最后，阻断花生四烯酸和 2-花生四烯酰甘油（两种主要内源性大麻素）降解的药理学阻断将 fmr1-/y LTD 恢复到野生型水平。这些发现为乙酰胆碱对伏隔核核心中兴奋性突触的复杂影响提供了新的认识，并确定了脆性 X 突触缺陷的新底物。
