Cuthbert Peter C, Stanford Lianne E, Coba Marcelo P, Ainge James A, Fink Ann E, Opazo Patricio, Delgado Jary Y, Komiyama Noboru H, O'Dell Thomas J, Grant Seth G N
Wellcome Trust Sanger Institute, Cambridge CB10 1SA, United Kingdom.
J Neurosci. 2007 Mar 7;27(10):2673-82. doi: 10.1523/JNEUROSCI.4457-06.2007.
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.
理解神经元如何解读动作电位模式中编码的信息的机制是认知心理学的核心。由与突触膜相关鸟苷酸激酶（MAGUK）蛋白（包括突触相关蛋白102（SAP102））相连的NMDA受体形成的多蛋白复合物在这些过程中发挥着重要作用。虽然携带SAP102突变的人类表现出智力迟钝，但其中涉及的生理和生化机制尚不清楚。利用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。这与空间学习的灵活性和损伤并行。尽管持续使用次优搜索策略，但通过额外训练，空间学习性能有所改善，并且在单独的非空间任务中，突变体再次采用了不同的策略。对突触后致密蛋白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。这些体内数据支持了特定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的突触活动模式以及哺乳动物神经系统中认知的不同方面提供了一种机制。
