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

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 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.

Keywords: CB1R; Synaptic plasticity; TRPV1R; accumbens; acetylcholine; endocannabinoid; fragile X; muscarinic receptors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholine / metabolism
  • Animals
  • Arachidonic Acids / metabolism
  • Carbachol / pharmacology
  • Cholinergic Agonists / pharmacology
  • Disease Models, Animal
  • Endocannabinoids / metabolism
  • Excitatory Postsynaptic Potentials
  • Fragile X Mental Retardation Protein / genetics
  • Fragile X Syndrome / metabolism*
  • Glycerides / metabolism
  • Long-Term Potentiation / drug effects
  • Long-Term Synaptic Depression / drug effects*
  • Mice
  • Neuronal Plasticity / drug effects
  • Nucleus Accumbens / drug effects*
  • Nucleus Accumbens / metabolism
  • Polyunsaturated Alkamides / metabolism
  • Receptor, Cannabinoid, CB1 / metabolism
  • Receptor, Muscarinic M1 / agonists*
  • Receptor, Muscarinic M1 / metabolism
  • Receptors, AMPA / metabolism
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • TRPV Cation Channels / metabolism


  • Arachidonic Acids
  • Cholinergic Agonists
  • Endocannabinoids
  • Fmr1 protein, mouse
  • Glycerides
  • Polyunsaturated Alkamides
  • Receptor, Cannabinoid, CB1
  • Receptor, Muscarinic M1
  • Receptors, AMPA
  • Receptors, N-Methyl-D-Aspartate
  • TRPV Cation Channels
  • TRPV1 protein, mouse
  • Fragile X Mental Retardation Protein
  • glyceryl 2-arachidonate
  • Carbachol
  • Acetylcholine
  • anandamide