Muscarinic M1 Receptor Modulation of Synaptic Plasticity in Nucleus Accumbens of Wild-Type and Fragile X Mice

We investigated how metabotropic acetylcholine receptors control excitatory synaptic plasticity in the mouse nucleus accumbens core. Pharmacological and genetic approaches revealed that M₁ mAChRs (muscarinic acetylcholine receptors) trigger multiple and interacting forms of synaptic plasticity. As previously described in the dorsal striatum, moderate pharmacological activation of M₁ mAChR potentiated postsynaptic NMDARs. The M₁-potentiation of NMDAR masked a previously unknown coincident TRPV1-mediated long-term depression (LTD). In addition, strong pharmacological activation of M₁ 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 M₁-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.