期刊
JOURNAL OF NEUROSCIENCE
卷 24, 期 45, 页码 10117-10127出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.3581-04.2004
关键词
acetylcholine; hippocampus; knock-out mice; learning and memory; long-term potentiation; muscarinic receptors; synaptic plasticity
Muscarinic acetylcholine receptors are known to play key roles in facilitating cognitive processes. However, the specific roles of the individual muscarinic receptor subtypes (M-1-M-5) in learning and memory are not well understood at present. In the present study, we used wild-type ( M2(+/+)) and M-2 receptor-deficient ( M2(-/-)) mice to examine the potential role of M-2 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 LTPm) 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.
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