Stability of surface NMDA receptors controls synaptic and behavioral adaptations to amphetamine.
Stability of surface NMDA receptors controls synaptic and behavioral adaptations to amphetamine.
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DOI：
10.1038/nn.2300
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发表时间：
2009-05
影响因子：
25
通讯作者：
Wang, John Q.
中科院分区：
文献类型：
--
作者：
Mao, Li-Min;Wang, Wei;Chu, Xiang-Ping;Zhang, Guo-Chi;Liu, Xian-Yu;Yang, Yuan-Jian;Haines, Michelle;Papasian, Christopher J.;Fibuch, Eugene E.;Buch, Shilpa;Chen, Jian-Guo;Wang, John Q.
谷氨酸能突触的可塑性变化导致持久的药物渴望和成瘾，人们对此知之甚少。通过对NMDA受体周转和转运的研究，我们发现长期暴露于精神刺激剂苯丙胺可诱导突触部位纹状体神经元受限表面膜池中NMDA受体NR2B亚单位的选择性下调。值得注意的是，这种下调是一个长期的事件，是由于泛素-蛋白酶体系统加速泛素化和降解关键的NR2B锚定蛋白而导致表面表达的NR2B不稳定的结果。突触NR2B的生化缺失进一步转化为突触可塑性的显著调节，表现为皮质-伏隔区谷氨酸能突触的长期抑制。在行为上，NR2B的遗传破坏诱导，而NR2B丢失的恢复防止对苯丙胺的行为敏感化。我们的数据表明，NR2B在兴奋性突触的重塑和对苯丙胺的持续精神运动可塑性的反应中是一个关键调节因子。
Plastic changes in glutamatergic synapses that lead to enduring drug craving and addiction are poorly understood. By focusing on the turnover and trafficking of NMDA receptors, we found that chronic exposure to the psychostimulant amphetamine induces selective downregulation of NMDA receptor NR2B subunits in the confined surface membrane pool of rat striatal neurons at synaptic sites. Remarkably, this downregulation is a long-lived event and results from the destabilization of surface-expressed NR2B due to accelerated ubiquitination and degradation of crucial NR2B-anchoring proteins by the ubiquitin-proteasome system. The biochemical loss of synaptic NR2B further translates to the significant modulation of synaptic plasticity in the form of long-term depression at cortico-accumbal glutamatergic synapses. Behaviorally, genetic disruption of NR2B induces, whereas restoration of NR2B loss prevents, behavioral sensitization to amphetamine. Our data identify NR2B as a key regulator in the remodeling of excitatory synapses and persistent psychomotor plasticity in response to amphetamine.
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影响因子：
25
作者：
Martin, Miquel;T Chen, Billy;Bonci, Antonello
通讯作者：
Bonci, Antonello
影响因子：
56.9
作者：
Brebner, K;Wong, TP;Wang, YT
通讯作者：
Wang, YT
影响因子：
4.7
作者：
Churchill, L;Swanson, CJ;Kalivas, PW
通讯作者：
Kalivas, PW
影响因子：
16.2
作者：
Liu, Xian-Yu;Chu, Xiang-Ping;Wang, John Q.
通讯作者：
Wang, John Q.
DOI：
10.1073/pnas.95.12.7097
发表时间：
1998-06-09
影响因子：
11.1
作者：
Lissin, DV;Gomperts, SN;von Zastrow, M
通讯作者：
von Zastrow, M