title: M2 muscarinic acetylcholine receptor knock-out mice show deficits in behavioral flexibility, working memory, and hippocampal plasticity.
abstract: 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.
authors.affiliation: Department of Physiology, University of Munich, D-80336 Munich, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Seeger
authors.forename: Irina
authors.initials: I
authors.lastname: Fedorova
authors.forename: Fang
authors.initials: F
authors.lastname: Zheng
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Miyakawa
authors.forename: Elena
authors.initials: E
authors.lastname: Koustova
authors.forename: Jesus
authors.initials: J
authors.lastname: Gomeza
authors.forename: Anthony S
authors.initials: AS
authors.lastname: Basile
authors.forename: Christian
authors.initials: C
authors.lastname: Alzheimer
authors.forename: Jürgen
authors.initials: J
authors.lastname: Wess
mesh_terms: D000647:Amnesia / Q000235:genetics / Q000503:physiopathology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology*; D001640:Bicuculline / Q000494:pharmacology; D002217:Carbachol / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D005703:Gallamine Triethiodide / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000503:physiopathology*; D017774:Long-Term Potentiation / Q000235:genetics / Q000502:physiology; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008568:Memory / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D018721:Muscarinic Agonists / Q000494:pharmacology; D009473:Neuronal Plasticity / Q000235:genetics / Q000502:physiology*; D018408:Patch-Clamp Techniques; D017966:Pyramidal Cells / Q000187:drug effects / Q000502:physiology; D043585:Receptor, Muscarinic M2 / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D011963:Receptors, GABA-A / Q000187:drug effects
chemical_list: D018721:Muscarinic Agonists; D043585:Receptor, Muscarinic M2; D011963:Receptors, GABA-A; D002217:Carbachol; D005703:Gallamine Triethiodide; D001640:Bicuculline