Terashima Akira, Pelkey Kenneth A, Rah Jong-Cheol, Suh Young Ho, Roche Katherine W, Collingridge Graham L, McBain Chris J, Isaac John T R
Developmental Synaptic Plasticity Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, 35 Convent Drive, Bethesda, MD 20892, USA.
Neuron. 2008 Mar 27;57(6):872-82. doi: 10.1016/j.neuron.2008.01.028.
PICK1 is a calcium-sensing, PDZ domain-containing protein that interacts with GluR2 and GluR3 AMPA receptor (AMPAR) subunits and regulates their trafficking. Although PICK1 has been principally implicated in long-term depression (LTD), PICK1 overexpression in CA1 pyramidal neurons causes a CaMK- and PKC-dependent potentiation of AMPAR-mediated transmission and an increase in synaptic GluR2-lacking AMPARs, mechanisms associated with NMDA receptor (NMDAR)-dependent long-term potentiation (LTP). Here, we directly tested whether PICK1 participates in both hippocampal NMDAR-dependent LTP and LTD. We show that the PICK1 potentiation of AMPAR-mediated transmission is NMDAR dependent and fully occludes LTP. Conversely, blockade of PICK1 PDZ interactions or lack of PICK1 prevents LTP. These observations demonstrate an important role for PICK1 in LTP. In addition, deletion of PICK1 or blockade of PICK1 PDZ binding prevented NMDAR-dependent LTD. Thus, PICK1 plays a critical role in bidirectional NMDAR-dependent long-term synaptic plasticity in the hippocampus.
PICK1是一种含PDZ结构域的钙敏感受体蛋白,它与AMPA受体(AMPAR)的GluR2和GluR3亚基相互作用并调节其转运。尽管PICK1主要与长时程抑制(LTD)有关,但在CA1锥体神经元中过表达PICK1会导致CaMK和PKC依赖的AMPAR介导的传递增强以及缺乏GluR2的突触性AMPAR增加,这些机制与NMDA受体(NMDAR)依赖的长时程增强(LTP)有关。在这里,我们直接测试了PICK1是否参与海马体中NMDAR依赖的LTP和LTD。我们发现,PICK1对AMPAR介导传递的增强作用依赖于NMDAR,并且完全阻断了LTP。相反,阻断PICK1的PDZ相互作用或缺乏PICK1会阻止LTP。这些观察结果证明了PICK1在LTP中起着重要作用。此外,缺失PICK1或阻断PICK1的PDZ结合会阻止NMDAR依赖的LTD。因此,PICK1在海马体中双向NMDAR依赖的长期突触可塑性中起关键作用。
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