Muscarinic acetylcholine receptor-dependent and NMDA receptor-dependent LTP and LTD share the common AMPAR trafficking pathway

The forebrain cholinergic system promotes higher brain function in part by signaling through the M(1) muscarinic acetylcholine receptor (mAChR). Long-term potentiation (LTP) and long-term depression (LTD) of excitatory synaptic transmission in the hippocampus are also induced by mAChR. An AMPA receptor (AMPAR) trafficking model for hippocampal neurons has been proposed to simulate N-methyl-D-aspartate receptor (NMDAR)-dependent synaptic plasticity in the early phase. In this study, we demonstrated the validity of the hypothesis that the mAChR-dependent LTP/LTD shares a common AMPAR trafficking pathway associated with NMDAR-dependent LTP/LTD. However, unlike NMDAR, Ca(2+) influx into the spine cytosol occurs owing to the Ca(2+) stored inside the ER and is induced via the activation of inositol 1,4,5-trisphosphate (IP3) receptors during M1 mAChR activation. Moreover, the AMPAR trafficking model implies that alterations in LTP and LTD observed in Alzheimer’s disease could be attributed to age-dependent reductions in AMPAR expression levels.