Prenatal cocaine reduces AMPA receptor synaptic expression through hyperphosphorylation of the synaptic anchoring protein GRIP

Kalindi Bakshi, Serena Gennaro, Christopher Y. Chan, Mary Kosciuk, Jing Jing Liu, Andres Stucky, Ekkehart Trenkner, Eitan Friedman, Robert G. Nagele, Hoau Yan Wang

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

Prenatal cocaine exposure produces sustained neurobehavioral and brain synaptic changes closely resembling those of animals with defective AMPA receptors (AMPARs). We hypothesized that prenatal cocaine exposure attenuates AMPAR signaling by interfering with AMPAR synaptic targeting. AMPAR function is governed by receptor cycling on and off the synaptic membrane through its interaction with glutamate receptor-interacting protein (GRIP), a PDZ domain protein that is regulated by reversible phosphorylation. Our results show that prenatal cocaine exposure markedly reduces AMPAR synaptic targeting and attenuates AMPAR-mediated synaptic long-term depression in the frontal cortex of 21-d-old rats. This cocaine effect is the result of reduced GRIP-AMPAR interaction caused by persistent phosphorylation of GRIP by protein kinase C (PKC) and Src tyrosine kinase. These data support the restoration of AMPAR activation via suppressing excessive PKC-mediated GRIP phosphorylation as a novel therapeutic approach to treat the neurobehavioral consequences of prenatal cocaine.

Original languageEnglish (US)
Pages (from-to)6308-6319
Number of pages12
JournalJournal of Neuroscience
Volume29
Issue number19
DOIs
StatePublished - May 13 2009

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)

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