Synapse-associated protein 102/dlgh3 couples the NMDA receptor to specific plasticity pathways and learning strategies.
Synapse-associated protein 102/dlgh3 couples the NMDA receptor to specific plasticity pathways and learning strategies.
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DOI：
10.1523/jneurosci.4457-06.2007
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发表时间：
2007-03-07
期刊：
影响因子：
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通讯作者：
Grant SG
中科院分区：
文献类型：
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作者：
Cuthbert PC;Stanford LE;Coba MP;Ainge JA;Fink AE;Opazo P;Delgado JY;Komiyama NH;O'Dell TJ;Grant SG
理解神经元解读动作电位模式中编码信息的机制是认知心理学的核心。由N - 甲基 - D - 天冬氨酸（NMDA）受体与突触膜相关鸟苷酸激酶（MAGUK）蛋白（包括突触相关蛋白102（SAP102）及其他相关蛋白）形成的多蛋白复合物在这些过程中起重要作用。尽管SAP102突变的人类表现出智力障碍，但所涉及的生理和生化机制尚不清楚。通过使用SAP102基因敲除小鼠，我们发现由特定刺激频率诱导的突触可塑性存在特定损伤，这也需要细胞外信号调节激酶信号传导。与此同时，空间学习出现僵化和损伤。尽管持续使用次优搜索策略，但通过额外训练，空间学习表现有所改善，并且在一个单独的非空间任务中，突变体再次采用了不同的策略。对突触后密度 - 95和SAP102突变体的双突变分析表明这两种MAGUK蛋白具有重叠和特定的功能。这些体内数据支持特定MAGUK蛋白将NMDA受体与不同下游信号通路偶联的模型。这为区分导致突触强度长期变化以及哺乳动物神经系统中不同认知方面的突触活动模式提供了一种机制。
Understanding the mechanisms whereby information encoded within patterns of action potentials is deciphered by neurons is central to cognitive psychology. The multiprotein complexes formed by NMDA receptors linked to synaptic membrane-associated guanylate kinase (MAGUK) proteins including synapse-associated protein 102 (SAP102) and other associated proteins are instrumental in these processes. Although humans with mutations in SAP102 show mental retardation, the physiological and biochemical mechanisms involved are unknown. Using SAP102 knock-out mice, we found specific impairments in synaptic plasticity induced by selective frequencies of stimulation that also required extracellular signal-regulated kinase signaling. This was paralleled by inflexibility and impairment in spatial learning. Improvement in spatial learning performance occurred with extra training despite continued use of a suboptimal search strategy, and, in a separate nonspatial task, the mutants again deployed a different strategy. Double-mutant analysis of postsynaptic density-95 and SAP102 mutants indicate overlapping and specific functions of the two MAGUKs. These in vivo data support the model that specific MAGUK proteins couple the NMDA receptor to distinct downstream signaling pathways. This provides a mechanism for discriminating patterns of synaptic activity that lead to long-lasting changes in synaptic strength as well as distinct aspects of cognition in the mammalian nervous system.