Article abstract
Nature Neuroscience 12, 602 - 610 (2009)
Published online: 6 April 2009 | doi:10.1038/nn.2300
Stability of surface NMDA receptors controls synaptic and behavioral adaptations to amphetamine
Li-Min Mao1,5, Wei Wang2,5, Xiang-Ping Chu1,5, Guo-Chi Zhang1, Xian-Yu Liu1, Yuan-Jian Yang2, Michelle Haines3, Christopher J Papasian1, Eugene E Fibuch3, Shilpa Buch4, Jian-Guo Chen2 & John Q Wang1,3
Abstract
Plastic changes in glutamatergic synapses that lead to endurance of drug craving and addiction are poorly understood. We examined the turnover and trafficking of NMDA receptors and found that chronic exposure to the psychostimulant amphetamine (AMPH) induced selective downregulation of NMDA receptor NR2B subunits in the confined surface membrane pool of rat striatal neurons at synaptic sites. This downregulation was a long-lived event and was a result of the destabilization of surface-expressed NR2B caused by accelerated ubiquitination and degradation of crucial NR2B-anchoring proteins by the ubiquitin-proteasome system. The biochemical loss of synaptic NR2B further translated to the modulation of synaptic plasticity in the form of long-term depression at cortico-accumbal glutamatergic synapses. Behaviorally, genetic disruption of NR2B induced and restoration of NR2B loss prevented behavioral sensitization to AMPH. Our data identify NR2B as an important regulator in the remodeling of excitatory synapses and persistent psychomotor plasticity in response to AMPH.
- Department of Basic Medical Science, University of Missouri Kansas City, School of Medicine, Kansas City, Missouri, USA.
- Department of Pharmacology and the Key Laboratory of Neurological Diseases of the Ministry of Education of China, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
- Department of Anesthesiology, University of Missouri Kansas City, School of Medicine, Kansas City, Missouri, USA.
- Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, Kansas, USA.
- These authors contributed equally to this work.
Correspondence to: Jian-Guo Chen2 e-mail: chenj@mails.tjmu.edu.cn
Correspondence to: John Q Wang1,3 e-mail: wangjq@umkc.edu
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