Activation of D1 dopamine receptors increases surface expression of AMPA receptors and facilitates their synaptic incorporation in cultured hippocampal neurons
Activation of D1 dopamine receptors increases surface expression of AMPA receptors and facilitates their synaptic incorporation in cultured hippocampal neurons
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DOI：
10.1111/j.1471-4159.2006.03999.x
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发表时间：
2006-09-01
影响因子：
4.7
通讯作者：
Wolf, Marina E.
中科院分区：
文献类型：
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作者：
Gao, Can;Sun, Xiu;Wolf, Marina E.
大量证据表明，导致成瘾的神经适应涉及相同的细胞过程，使学习和记忆，如长时程增强(LTP)，以及精神刺激剂影响LTP通过多巴胺(DA)依赖的机制。在海马CA1区锥体神经元中，LTP涉及alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate受体插入兴奋性突触。我们用分离培养的方法验证了D1族DA受体通过调节AMPA受体转运而影响海马神经元突触可塑性的假说。短暂暴露(5分钟)的D1激动剂可增加谷氨酸受体(GluR)1-AMPA受体在突触外部位的外化率，从而增加其表面表达。这需要分泌途径，而不是蛋白质合成，主要由蛋白激酶A(PKA)介导，钙-钙调蛋白依赖性蛋白激酶II(CaMKII)的贡献较小。预先刺激D1R可促进突触插入GluR1，以响应随后用甘氨酸刺激突触NMDA受体的反应。我们的结果支持突触GluR1掺入模型，在该模型中，PKA最初需要插入突触外膜，而CaMKII介导转位到突触内。通过增加突触外GluR1池的大小，D1受体可能促进LTP。精神刺激剂可能会篡夺这一机制，导致不适当的可塑性，从而导致与成瘾相关的行为。
Considerable evidence indicates that neuroadaptations leading to addiction involve the same cellular processes that enable learning and memory, such as long-term potentiation (LTP), and that psychostimulants influence LTP through dopamine (DA)-dependent mechanisms. In hippocampal CA1 pyramidal neurons, LTP involves insertion of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptors into excitatory synapses. We used dissociated cultures to test the hypothesis that D1 family DA receptors influence synaptic plasticity in hippocampal neurons by modulating AMPA receptor trafficking. Brief exposure (5 min) to a D1 agonist increased surface expression of glutamate receptor (GluR)1-containing AMPA receptors by increasing their rate of externalization at extrasynaptic sites. This required the secretory pathway but not protein synthesis, and was mediated mainly by protein kinase A (PKA) with a smaller contribution from Ca2+-calmodulin-dependent protein kinase II (CaMKII). Prior D1 receptor stimulation facilitated synaptic insertion of GluR1 in response to subsequent stimulation of synaptic NMDA receptors with glycine. Our results support a model for synaptic GluR1 incorporation in which PKA is required for initial insertion into the extrasynaptic membrane whereas CaMKII mediates translocation into the synapse. By increasing the size of the extrasynaptic GluR1 pool, D1 receptors may promote LTP. Psychostimulants may usurp this mechanism, leading to inappropriate plasticity that contributes to addiction-related behaviors.