Title : M2 muscarinic acetylcholine receptor knock-out mice show deficits in behavioral flexibility, working memory, and hippocampal plasticity - Seeger_2004_J.Neurosci_24_10117 |
Author(s) : Seeger T , Fedorova I , Zheng F , Miyakawa T , Koustova E , Gomeza J , Basile AS , Alzheimer C , Wess J |
Ref : Journal of Neuroscience , 24 :10117 , 2004 |
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. |
PubMedSearch : Seeger_2004_J.Neurosci_24_10117 |
PubMedID: 15537882 |
Seeger T, Fedorova I, Zheng F, Miyakawa T, Koustova E, Gomeza J, Basile AS, Alzheimer C, Wess J (2004)
M2 muscarinic acetylcholine receptor knock-out mice show deficits in behavioral flexibility, working memory, and hippocampal plasticity
Journal of Neuroscience
24 :10117
Seeger T, Fedorova I, Zheng F, Miyakawa T, Koustova E, Gomeza J, Basile AS, Alzheimer C, Wess J (2004)
Journal of Neuroscience
24 :10117