Identification of PSD-95 as a regulator of dopamine-mediated synaptic and behavioral plasticity

被引:302
作者
Yao, WD
Gainetdinov, RR
Arbuckle, MI
Sotnikova, TD
Cyr, M
Beaulieu, JM
Torres, GE
Grant, SGN
Caron, MG [1 ]
机构
[1] Duke Univ, Howard Hughes Med Inst Labs, Ctr Med, Dept Cell Biol, Durham, NC 27710 USA
[2] Univ Edinburgh, Div Neurosci, Edinburgh EH8 9J2, Midlothian, Scotland
[3] Wellcome Trust Sanger Inst, Hinxton CB10 1SA, Cambs, England
关键词
D O I
10.1016/S0896-6273(04)00048-0
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
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 fronto-cortico-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.
引用
收藏
页码:625 / 638
页数:14
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