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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Yao, W-D; Gainetdinov, RR; Arbuckle, MI; Sotnikova, TD; Cyr, M; Beaulieu, J-M; Torres, GE; Grant, SGN; Caron, MG

Published Date

  • February 19, 2004

Published In

Volume / Issue

  • 41 / 4

Start / End Page

  • 625 - 638

PubMed ID

  • 14980210

Pubmed Central ID

  • 14980210

International Standard Serial Number (ISSN)

  • 0896-6273

Language

  • eng

Conference Location

  • United States