Colocalization of M1 muscarinic cholinergic receptors and NMDA receptors in dendrites and spines of pyramidal neurons of the mouse basolateral amygdala: An ultrastructural analysis.

The cholinergic innervation of the neocortex, hippocampus, and basolateral amygdala is critical for higher cognitive functions, including attention and memory. One action of ACh in the hippocampus is the potentiation of NMDA receptor (NMDAR) currents in pyramidal neurons (PNs) by M1 muscarinic receptors (M1Rs). The increase in these currents enhances long-term potentiation (LTP), an important mechanism for memory formation. Ultrastructural observations in the hippocampus revealed that M1Rs and NMDARs were colocalized in hippocampal PN dendrites, consistent with electrophysiological studies demonstrating M1R-NMDAR interactions. Similar to the hippocampus, activation of M1Rs have been shown to be critical for mnemonic functions in the anterior basolateral nucleus of the amygdala (BLa). In the present study dual-labeling immunoelectron microscopy was used to determine if there was colocalization of M1Rs and NMDARs in neurons of the mouse BLa. We found extensive colocalization of these receptors in dendrites and spines of BLa PNs, and most of the M1Rs were membrane-associated where they could be activated by released acetylcholine. These results suggest that M1Rs in BLa PNs could be targeted by M1R positive allosteric modulators (PAMs), resulting in amelioration of memory impairments in neuropsychiatric disorders, such as Alzheimer's disease, by potentiating NMDAR currents in the amygdala.