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The Journal of Neuroscience, November 10, 2004, 24(45):10117-10127; doi:10.1523/JNEUROSCI.3581-04.2004

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Behavioral/Systems/Cognitive
M₂ Muscarinic Acetylcholine Receptor Knock-Out Mice Show Deficits in Behavioral Flexibility, Working Memory, and Hippocampal Plasticity

Thomas Seeger,^1 * Irina Fedorova,^2 * Fang Zheng,^4 * Tsuyoshi Miyakawa,⁵ Elena Koustova,² Jesus Gomeza,³ Anthony S. Basile,² Christian Alzheimer,^1,4 and Jürgen Wess³

¹Department of Physiology, University of Munich, D-80336 Munich, Germany, ²Neuroscience Group and ³Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, ⁴Department of Physiology, University of Kiel, D-24098 Kiel, Germany, and ⁵Laboratory for Genetic Engineering and Functional Genomics, Kyoto University Faculty of Medicine, Kyoto 606-8501, Japan

Muscarinic acetylcholine receptors are known to play key roles in facilitating cognitive processes. However, the specific roles of the individual muscarinic receptor subtypes (M₁-M₅) in learning and memory are not well understood at present. In the present study, we used wild-type (M2^+/+) and M₂ receptor-deficient (M2^-/-) mice to examine the potential role of M₂ receptors in learning and memory and hippocampal synaptic plasticity. M2^-/- mice showed significant deficits in behavioral flexibility and working memory in the Barnes circular maze and the T-maze delayed alternation tests, respectively. The behavioral deficits of M2^-/- mice were associated with profound changes in neuronal plasticity studied at the Schaffer-CA1 synapse of hippocampal slices. Strikingly, short-term potentiation (STP) was abolished, and long-term potentiation (LTP) was drastically reduced after high-frequency stimulation of M2^-/- hippocampi. Treatment of M2^-/- hippocampal slices with the GABA_A receptor antagonist, bicuculline, restored STP and significantly increased LTP. Whole-cell recordings from CA1 pyramidal cells demonstrated a much stronger disinhibition of GABAergic than glutamatergic transmission in M2^-/- hippocampi, which was particularly prominent during stimulus trains. Increased strength of GABAergic inhibition is thus a likely mechanism underlying the impaired synaptic plasticity observed with M2^-/- hippocampi. Moreover, the persistent enhancement of excitatory synaptic transmission in CA1 pyramidal cells induced by the transient application of a low concentration of a muscarinic agonist (referred to as LTP_m) was totally abolished in M2^-/- mice. Because impaired muscarinic cholinergic neurotransmission is associated with Alzheimer's disease and normal aging processes, these findings should be of considerable therapeutic relevance.

Key words: acetylcholine; hippocampus; knock-out mice; learning and memory; long-term potentiation; muscarinic receptors; synaptic plasticity

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Received June 12, 2003; revised September 29, 2004; accepted September 30, 2004.

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