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The Journal of Neuroscience, May 13, 2009, 29(19):6308-6319; doi:10.1523/JNEUROSCI.5485-08.2009

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Development/Plasticity/Repair
Prenatal Cocaine Reduces AMPA Receptor Synaptic Expression through Hyperphosphorylation of the Synaptic Anchoring Protein GRIP

Kalindi Bakshi,^1,2,3 Serena Gennaro,^1,5 Christopher Y. Chan,^1,2 Mary Kosciuk,⁴ JingJing Liu,^1,2 Andres Stucky,^1,2 Ekkehart Trenkner,^2,3 Eitan Friedman,^1,2 Robert G. Nagele,⁴ and Hoau-Yan Wang^1,2

¹Departments of Physiology and Pharmacology, Sophie Davis School of Biomedical Education, The City University of New York Medical School, New York, New York 10031, ²Department of Biology and Neuroscience, Graduate School of The City University of New York, New York, New York 10061, ³College of Staten Island, Institute for Basic Research Center for Developmental Neuroscience, The City University of New York, New York, New York 10314, ⁴New Jersey Institute for Successful Aging, University of Medicine and Dentistry of New Jersey–School of Osteopathic Medicine, Stratford, New Jersey 08084, and ⁵Department of Neurological, Psychiatric, and Anesthesiological Sciences, University of Messina, 1-98122 Messina, Italy

Correspondence should be addressed to Dr. Hoau-Yan Wang, Department of Physiology and Pharmacology, The City University of New York Medical School, H-210F, Harris Hall, 138th Street and Convent Avenue, New York, NY 10031. Email: hywang{at}sci.ccny.cuny.edu

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.

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Received Nov. 13, 2008; revised March 3, 2009; accepted April 1, 2009.

Correspondence should be addressed to Dr. Hoau-Yan Wang, Department of Physiology and Pharmacology, The City University of New York Medical School, H-210F, Harris Hall, 138th Street and Convent Avenue, New York, NY 10031. Email: hywang{at}sci.ccny.cuny.edu

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