Prenatal cocaine reduces AMPA receptor synaptic expression through hyperphosphorylation of the synaptic anchoring protein GRIP.
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.
Bakshi
Kalindi
K
Department of Physiology, The City University of New York Medical School, New York, New York 10031, USA.
Gennaro
Serena
S
Chan
Christopher Y
CY
Kosciuk
Mary
M
Liu
Jingjing
J
Stucky
Andres
A
Trenkner
Ekkehart
E
Friedman
Eitan
E
Nagele
Robert G
RG
Wang
Hoau-Yan
HY
D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D002491:Central Nervous System Agents / Q000633:toxicity*; D003042:Cocaine / Q000633:toxicity*; D005260:Female; D005625:Frontal Lobe / Q000187:drug effects / Q000254:growth & development; D015870:Gene Expression / Q000187:drug effects; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins; D036881:Long-Term Synaptic Depression / Q000187:drug effects / Q000502:physiology; D008297:Male; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000378:metabolism*; D013569:Synapses / Q000187:drug effects* / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
D002352:Carrier Proteins; D002491:Central Nervous System Agents; C491308:Grip1 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D018091:Receptors, AMPA; D019061:src-Family Kinases; D011493:Protein Kinase C; D003042:Cocaine