Yao Wei-Dong, Gainetdinov Raul R, Arbuckle Margaret I, Sotnikova Tatyana D, Cyr Michel, Beaulieu Jean-Martin, Torres Gonzalo E, Grant Seth G N, Caron Marc G
Howard Hughes Medical Institute Laboratories, Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA.
Neuron. 2004 Feb 19;41(4):625-38. doi: 10.1016/s0896-6273(04)00048-0.
To identify the molecular mechanisms underlying psychostimulant-elicited plasticity in the brain reward system, we undertook a phenotype-driven approach using genome-wide microarray profiling of striatal transcripts from three genetic and one pharmacological mouse models of psychostimulant or dopamine supersensitivity. A small set of co-affected genes was identified. One of these genes encoding the synaptic scaffolding protein PSD-95 is downregulated in the striatum of all three mutants and in chronically, but not acutely, cocaine-treated mice. At the synaptic level, enhanced long-term potentiation (LTP) of the frontocortico-accumbal glutamatergic synapses correlates with PSD-95 reduction in every case. Finally, targeted deletion of PSD-95 in an independent line of mice enhances LTP, augments the acute locomotor-stimulating effects of cocaine, but leads to no further behavioral plasticity in response to chronic cocaine. Our findings uncover a previously unappreciated role of PSD-95 in psychostimulant action and identify a molecular and cellular mechanism shared between drug-related plasticity and learning.
为了确定大脑奖赏系统中精神兴奋剂引发可塑性的分子机制，我们采用了一种表型驱动的方法，对来自精神兴奋剂或多巴胺超敏反应的三种遗传和一种药理学小鼠模型的纹状体转录本进行全基因组微阵列分析。鉴定出了一小部分共同受影响的基因。其中一个编码突触支架蛋白PSD-95的基因在所有三个突变体的纹状体中以及在长期（而非急性）接受可卡因治疗的小鼠中表达下调。在突触水平上，前额叶皮质-伏隔核谷氨酸能突触的增强的长时程增强（LTP）在每种情况下都与PSD-95的减少相关。最后，在一个独立的小鼠品系中靶向缺失PSD-95会增强LTP，增强可卡因的急性运动刺激作用，但对慢性可卡因没有进一步的行为可塑性反应。我们的研究结果揭示了PSD-95在精神兴奋剂作用中以前未被认识到的作用，并确定了药物相关可塑性和学习之间共享的分子和细胞机制。
