M1 muscarinic receptor facilitates cognitive function by interplay with AMPA receptor GluA1 subunit

Abstract

Background: M1 muscarinic acetylcholine receptors (M1 mAChRs) are the most abundant muscarinic receptors in the hippocampus and shown to have procognitive effects. AMPA receptors (AMPARs), an important subtype of ionotropic glutamate receptors, are key components in neurocognitive networks. However, how AMPAR affects M1R-mediated learning and memory is still elusive. Methods: The expression and synaptic insertion of GluA1, one of the subunits of AMPARs, after manipulation of M1 mAChRs were determined by surface biotinylation, live cell imaging and postsynaptic density fractionations. The M1 mAChR-mediated learning and memory were assessed in mice deficient of GluA1 phosphorylation at Ser845. Results: Basal expression of GluA1, and its phosphorylation at Ser845 were maintained by M1 mAChR activity. Activation of M1 mAChRs promoted membrane insertion of GluA1, especially to postsynaptic densities. Impairment of hippocampus-dependent learning and memory by antagonism of M1 mAChRs was paralleled to the reduction of GluA1 expression, meanwhile improvement of learning and memory by activation of M1 mAChRs was accompanied by the synaptic insertion of GluA1 and its increased phosphorylation at Ser845. Furthermore, abrogation of phosphorylation of Ser845 residue of GluA1 ablated M1 mAChR-mediated improvement of learning and memory. Conclusions: The study demonstrates a functional correlation of M1 mAChRs and GluA1 and the essential role of GluA1 in M1 mAChR-mediated cognitive improvement, providing new insight into the mechanisms in which M1R agonists could rescue the cognitive dysfunction.[This work was supported by International Science & Technology Cooperation Program of China (2011DFA33180), National Natural Science Foundation of China (81473217)]