Selective cognitive dysfunction in acetylcholine M1 muscarinic receptor mutant mice.
Blockade of cholinergic neurotransmission by muscarinic receptor antagonists produces profound deficits in attention and memory. However, the antagonists used in previous studies bind to more than one of the five muscarinic receptor subtypes. Here we examined memory in mice with a null mutation of the gene coding the M1 receptor, the most densely distributed muscarinic receptor in the hippocampus and forebrain. In contrast with previous studies using nonselective pharmacological antagonists, the M1 receptor deletion produced a selective phenotype that included both enhancements and deficits in memory. Long-term potentiation (LTP) in response to theta burst stimulation in the hippocampus was also reduced in mutant mice. M1 null mutant mice showed normal or enhanced memory for tasks that involved matching-to-sample problems, but they were severely impaired in non-matching-to-sample working memory as well as consolidation. Our results suggest that the M1 receptor is specifically involved in memory processes for which the cortex and hippocampus interact.
Anagnostaras
Stephan G
SG
Department of Neurobiology, Brain Research Institute, 2554 Gonda Center, Box 951761, University of California, Los Angeles, California 90095-1761, USA.
Murphy
Geoffrey G
GG
Hamilton
Susan E
SE
Mitchell
Scott L
SL
Rahnama
Nancy P
NP
Nathanson
Neil M
NM
Silva
Alcino J
AJ
D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism* / Q000503:physiopathology; D003213:Conditioning, Psychological / Q000502:physiology; D003463:Cues; D004193:Discrimination Learning / Q000502:physiology; D004558:Electric Stimulation; D005239:Fear / Q000502:physiology; D005260:Female; D006624:Hippocampus / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D018782:Maze Learning / Q000502:physiology; D008568:Memory / Q000502:physiology; D008569:Memory Disorders / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D008570:Memory, Short-Term / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009434:Neural Pathways / Q000378:metabolism* / Q000503:physiopathology; D010641:Phenotype; D043643:Receptor, Muscarinic M1; D011976:Receptors, Muscarinic / Q000172:deficiency* / Q000235:genetics
D043643:Receptor, Muscarinic M1; D011976:Receptors, Muscarinic; D000109:Acetylcholine