title: Delivery of AMPA receptors to perisynaptic sites precedes the full expression of long-term potentiation.
abstract: Trafficking of AMPA subtype glutamate receptors (AMPARs) from intracellular compartments to synapses is thought to be a major mechanism underlying the expression of long-term potentiation (LTP), a cellular substrate for learning and memory. However, it remains unclear whether the AMPAR trafficking that takes place during LTP is due to a targeted insertion of AMPARs directly into the synapse or delivery to extrasynaptic sites followed by translocation into the synapse. Here, we provide direct physiological evidence that LTP induced by a theta-burst pairing and tetanic stimulation protocols causes the rapid delivery of AMPARs to a perisynaptic site. Perisynaptic AMPARs do not normally detect synaptically released glutamate but can do so when the glial glutamate transporter EAAT1 is inhibited. AMPARs can be detected at this perisynaptic site before, but not after, the full expression of LTP. The appearance of perisynaptic AMPARs requires postsynaptic exocytosis, PKA signaling, and the C-terminal region of GluR1 subunit of AMPARs but not actin polymerization. Actin polymerization after LTP induction is required to retain AMPARs at the perisynaptic site after their appearance. Low-frequency stimulation given shortly after LTP induction leads to activity-dependent removal of perisynaptic AMPARs and suppresses the subsequent expression of LTP. These results demonstrate that AMPARs are rapidly trafficked to perisynaptic sites shortly after LTP induction and suggest that the delivery and maintenance of perisynaptic AMPARs may serve as a checkpoint in the expression of LTP.
authors.affiliation: Department of Neurology, Mount Sinai School of Medicine, New York, NY 10029, USA.
authors.forename: Yunlei
authors.initials: Y
authors.lastname: Yang
authors.forename: Xiao-Bin
authors.initials: XB
authors.lastname: Wang
authors.forename: Matthew
authors.initials: M
authors.lastname: Frerking
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhou
mesh_terms: D000818:Animals; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D027341:Excitatory Amino Acid Transporter 1 / Q000378:metabolism; D005089:Exocytosis / Q000502:physiology; D007858:Learning / Q000502:physiology*; D017774:Long-Term Potentiation / Q000502:physiology*; D021381:Protein Transport / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013569:Synapses / Q000378:metabolism*
chemical_list: D027341:Excitatory Amino Acid Transporter 1; D018091:Receptors, AMPA; C493392:Slc1a3 protein, rat; D017868:Cyclic AMP-Dependent Protein Kinases