Scott Lena, Zelenin Sergey, Malmersjö Seth, Kowalewski Jacob M, Markus Eivor Zettergren, Nairn Angus C, Greengard Paul, Brismar Hjalmar, Aperia Anita
Department of Woman and Child Health, Karolinska Institutet, Astrid Lindgren Children's Hospital Q2:09, S-171 76 Stockholm, Sweden.
Proc Natl Acad Sci U S A. 2006 Jan 17;103(3):762-7. doi: 10.1073/pnas.0505557103. Epub 2006 Jan 9.
The dopaminergic and glutamatergic systems interact to initiate and organize normal behavior, a communication that may be perturbed in many neuropsychiatric diseases, including schizophrenia. We show here that NMDA, by allosterically modifying NMDA receptors, can act as a scaffold to recruit laterally diffusing dopamine D1 receptors (D1R) to neuronal spines. Using organotypic culture from rat striatum transfected with D1R fused to a fluorescent protein, we show that the majority of dendritic D1R are in lateral diffusion and that their mobility is confined by interaction with NMDA receptors. Exposure to NMDA reduces the diffusion coefficient for D1R and causes an increase in the number of D1R-positive spines. Unexpectedly, the action of NMDA in potentiating D1R recruitment was independent of calcium flow via the NMDA receptor channel. Thus, a highly energy-efficient, diffusion-trap mechanism can account for intraneuronal interaction between the glutamatergic and dopaminergic systems and for regulation of the number of D1R-positive spines. This diffusion trap system represents a molecular mechanism for brain plasticity and offers a promising target for development of antipsychotic therapy.
多巴胺能系统和谷氨酸能系统相互作用以启动和组织正常行为，这种交流在包括精神分裂症在内的许多神经精神疾病中可能会受到干扰。我们在此表明，NMDA通过变构修饰NMDA受体，可作为一种支架，将侧向扩散的多巴胺D1受体（D1R）募集到神经元棘突。利用转染了与荧光蛋白融合的D1R的大鼠纹状体器官型培养物，我们表明大多数树突状D1R处于侧向扩散状态，并且它们的移动性受到与NMDA受体相互作用的限制。暴露于NMDA会降低D1R的扩散系数，并导致D1R阳性棘突数量增加。出乎意料的是，NMDA增强D1R募集的作用独立于通过NMDA受体通道的钙流。因此，一种高效节能的扩散陷阱机制可以解释谷氨酸能系统和多巴胺能系统之间的神经元内相互作用以及D1R阳性棘突数量的调节。这种扩散陷阱系统代表了大脑可塑性的分子机制，并为抗精神病治疗的发展提供了一个有前景的靶点。
