D‐Cycloserine facilitates synaptic plasticity but impairs glutamatergic neurotransmission in rat hippocampal slices
D‐Cycloserine facilitates synaptic plasticity but impairs glutamatergic neurotransmission in rat hippocampal slices
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DOI：
10.1038/sj.bjp.0705541
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发表时间：
2003-11
影响因子：
7.3
通讯作者：
E. Rouaud;J. Billard
中科院分区：
文献类型：
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作者：
E. Rouaud;J. Billard
谷氨酸能 N-甲基-D-天冬氨酸受体亚型 (NMDAr) 的甘氨酸结合位点已被提议作为治疗神经退行性疾病和精神分裂症认知障碍的假定靶点。尽管已经积累的行为证据表明部分激动剂D-环丝氨酸（DCS）促进学习和记忆，但该药物的生理机制仍有待表征。在本研究中，我们利用细胞外场兴奋性突触后电位研究了 DCS 对大鼠海马切片 CA1 区谷氨酸神经传递和突触可塑性的影响。我们发现 DCS 促进了 NMDAr 介导的突触电位。此外，我们发现激动剂显着增强了NMDA依赖性长期抑制的程度，同时诱导持久增强的阈值降低。我们发现DCS减少了谷氨酸受体的α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）/红藻氨酸亚型介导的神经传递。这种抑制不能被γ-氨基丁酸GABAA拮抗剂荷包牡丹碱阻止，而是被甘氨酸拮抗剂马钱子碱拮抗。因此，这些结果显示DCS对海马内NMDA和非NMDA突触反应的相反作用。他们还证明 DCS 促进长期突触可塑性，这可能支持 DCS 诱导的认知表现增强。英国药理学杂志 (2003)140, 1051–1056。 doi:10.1038/sj.bjp.0705541
The glycine‐binding site of the glutamatergicN‐methyl‐D‐aspartate receptor subtype (NMDAr) has been proposed as a putative target for treating cognitive impairments in neurodegenerative disorders and schizophrenia. Although behavioural evidence has been accumulated showing that the partial agonistD‐cycloserine (DCS) facilitated learning and memory, physiological mechanisms of the drug still remained to be characterized. In the present study, we have investigated the effects of DCS on glutamatergic neurotransmission and synaptic plasticity in CA1 region of rat hippocampal slices, using extracellular field excitatory postsynaptic potentials.We showed that DCS facilitated NMDAr‐mediated synaptic potentials. In addition, we found that the magnitude of NMDAr‐dependent long‐term depression was significantly enhanced by the agonist, while the threshold for the induction of lasting potentiations was lowered.We found that DCS decreased neurotransmission mediated byα‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA)/kainate subtypes of glutamate receptors. This inhibition was not prevented by theγ‐aminobutyric acid GABAAantagonist bicuculline, but was antagonized by the glycine antagonist strychnine.These results, therefore, show opposite effects of DCS on NMDA and non‐NMDA synaptic responses within the hippocampus. They also demonstrate that DCS facilitates long‐term synaptic plasticity that may support the DCS‐induced enhanced cognitive performances.British Journal of Pharmacology(2003)140, 1051–1056. doi:10.1038/sj.bjp.0705541