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Selective cognitive dysfunction in acetylcholine M1 muscarinic receptor mutant mice

Nature Neuroscience volume 6, pages 51–58 (2003)Cite this article

Abstract

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.

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Figure 1: Pavlovian contextual and cued fear conditioning.
Figure 2: Win-shift spatial working memory, social discrimination and Morris water maze learning.
Figure 3: Generalized activity and motor performance.
Figure 4: Hippocampal CA1 long-term potentiation (LTP) in vitro.

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Acknowledgements

Supported by National Institutes of Health grants to S.A. (F32 NS10932), G.M. (F32 AG5858), N.N. (R01 NS26920) and A.S. (R01 AG17499). We thank R. Costa, A. Matynia, J. Sage and M. Sanders for comments on this manuscript.

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Authors and Affiliations

  1. Departments of Neurobiology, Psychology, and Psychiatry, Brain Research Institute, 2554 Gonda Center, Box 951761, University of California, Los Angeles, 90095-1761, California, USA

    Stephan G. Anagnostaras, Geoffrey G. Murphy, Scott L. Mitchell, Nancy P. Rahnama & Alcino J. Silva

  2. Department of Psychology, Emory University, and Center for Behavioral Neuroscience, 532 N. Kilgo Circle, Atlanta, 30322, Georgia, USA

    Stephan G. Anagnostaras & Scott L. Mitchell

  3. Department of Pharmacology, University of Washington, K536A Health Sciences Building, Box 357750, Seattle, 98195-7750, Washington, USA

    Susan E. Hamilton & Neil M. Nathanson

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Correspondence to Alcino J. Silva.

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Anagnostaras, S., Murphy, G., Hamilton, S. et al. Selective cognitive dysfunction in acetylcholine M1 muscarinic receptor mutant mice. Nat Neurosci 6, 51–58 (2003). https://doi.org/10.1038/nn992

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