Identification of PSD-95 as a regulator of dopamine-mediated synaptic and behavioral plasticity.
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.
Yao
Wei-Dong
WD
Howard Hughes Medical Institute Laboratories, Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA.
Gainetdinov
Raul R
RR
Arbuckle
Margaret I
MI
Sotnikova
Tatyana D
TD
Cyr
Michel
M
Beaulieu
Jean-Martin
JM
Torres
Gonzalo E
GE
Grant
Seth G N
SG
Caron
Marc G
MG
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D003042:Cocaine / Q000494:pharmacology; D019970:Cocaine-Related Disorders / Q000235:genetics; D000076122:Disks Large Homolog 4 Protein; D004298:Dopamine / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D051528:Guanylate Kinases; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins; D017774:Long-Term Potentiation / Q000235:genetics; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D009434:Neural Pathways / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D012333:RNA, Messenger / Q000378:metabolism; D012201:Reward; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology
D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; C033652:postsynaptic density proteins; D051528:Guanylate Kinases; D003042:Cocaine; D004298:Dopamine