ACTIVATION OF THE GENETICALLY DEFINED M1 MUSCARINIC RECEPTOR POTENTIATES N-METHYL-D-ASPARTATE (NMDA) RECEPTOR CURRENTS IN HIPPOCAMPAL PYRAMIDAL CELLS

Evidence suggests that cholinergic input to the hippocampus plays an i mportant role in learning and memory and that degeneration of choliner gic terminals in the hippocampus may contribute to the memory loss ass ociated with Alzheimer's disease. One of the more prominent effects of cholinergic agonists on hippocampal physiology is the potentiation of N-methyl-D-aspartate (NMDA)-receptor currents by muscarinic agonists, Here, we employ traditional pharmacological reagents as well as ml-to xin, an mi antagonist with unprecedented selectivity, to demonstrate t hat this potentiation of NMDA-receptor currents in hippocampal CA1 pyr amidal cells is mediated by the genetically defined mi muscarinic rece ptor. Furthermore, we demonstrate the colocalization of the mi muscari nic receptor and the NR1a NMDA receptor subunit at the electron micros copic level, indicating a spatial relationship that would allow for ph ysiological interactions between these two receptors, This work demons trates that the ml-muscarinic receptor gene product modulates excitato ry synaptic transmission, and it has important implications in the stu dy of learning and memory as well as the design of drugs to treat neur odegenerative diseases such as Alzheimer's.