Seeger Thomas, Fedorova Irina, Zheng Fang, Miyakawa Tsuyoshi, Koustova Elena, Gomeza Jesus, Basile Anthony S, Alzheimer Christian, Wess Jürgen
Department of Physiology, University of Munich, D-80336 Munich, Germany.
J Neurosci. 2004 Nov 10;24(45):10117-27. doi: 10.1523/JNEUROSCI.3581-04.2004.
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.
已知毒蕈碱型乙酰胆碱受体在促进认知过程中发挥关键作用。然而，目前对于各个毒蕈碱受体亚型（M1 - M5）在学习和记忆中的具体作用尚不清楚。在本研究中，我们使用野生型（M2 +/+）和M2受体缺陷型（M2 -/-）小鼠来研究M2受体在学习、记忆和海马突触可塑性中的潜在作用。M2 -/-小鼠在巴恩斯圆形迷宫和T迷宫延迟交替试验中分别表现出行为灵活性和工作记忆的显著缺陷。M2 -/-小鼠的行为缺陷与海马切片的Schaffer - CA1突触处研究的神经元可塑性的深刻变化有关。令人惊讶的是，在高频刺激M2 -/-海马后，短期增强（STP）被消除，长期增强（LTP）大幅降低。用GABA(A)受体拮抗剂荷包牡丹碱处理M2 -/-海马切片可恢复STP并显著增加LTP。来自CA1锥体细胞的全细胞记录表明，在M2 -/-海马中，GABA能传递的去抑制作用比谷氨酸能传递更强，这在刺激序列期间尤为突出。因此，GABA能抑制增强可能是M2 -/-海马中观察到的突触可塑性受损的潜在机制。此外，在M2 -/-小鼠中，短暂应用低浓度毒蕈碱激动剂诱导的CA1锥体细胞兴奋性突触传递的持续增强（称为LTP(m)）完全被消除。由于毒蕈碱胆碱能神经传递受损与阿尔茨海默病和正常衰老过程相关，这些发现应具有相当大的治疗意义。
