title: Calcium-Permeable AMPA Receptors Mediate the Induction of the Protein Kinase A-Dependent Component of Long-Term Potentiation in the Hippocampus.
abstract: Two forms of NMDA receptor (NMDAR)-dependent long-term potentiation (LTP) at hippocampal CA1 synapses can be distinguished based on their sensitivity to inhibitors of protein kinase A (PKA). The PKA-dependent form requires multiple episodes of high-frequency stimulation (HFS) or theta burst stimuli (TBS) with a spacing between episodes in the order of minutes. To investigate the mechanism by which spaced episodes induce the PKA-dependent form of LTP, we have compared, in interleaved experiments, spaced (s) and compressed (c) TBS protocols in the rat CA1 synapses. We find that LTP induced by sTBS, but not that induced by cTBS, involves the insertion of calcium-permeable (CP) AMPARs, as assessed using pharmacological and electrophysiological criteria. Furthermore, a single TBS when paired with rolipram [4-(3-(cyclopentyloxy)-4-methoxyphenyl)pyrrolidin-2-one], to activate PKA, generates an LTP that also involves the insertion of CP-AMPARs. These data demonstrate that the involvement of CP-AMPARs in LTP is critically determined by the timing of the induction trigger and is associated specifically with the PKA-dependent form of LTP.
  
  
  CONCLUSIONS
  Long-term potentiation is a family of synaptic mechanisms that are believed to be important for learning and memory. Two of the most extensively studied forms are triggered by the synaptic activation of NMDA receptors and expressed by changes in AMPA receptor function. They can be distinguished on the basis of their requirement for activation of a protein kinase, PKA. We show that the PKA-dependent form also involves the transient insertion of calcium-permeable AMPA receptors. These results have implications for relating synaptic plasticity to learning and memory and suggest a specific linkage between PKA activation and the rapid synaptic insertion of calcium-permeable AMPA receptors during long-term potentiation.
authors.affiliation: Department of Biological Sciences and Brain and Cognitive Sciences, College of Natural Sciences, Seoul National University, Seoul 08826, Korea, Centre for Synaptic Plasticity, School of Physiology and Pharmacology, Bristol BS1 3NY, United Kingdom.
authors.forename: Pojeong
authors.identifier: http://orcid.org/0000-0002-5574-6104
authors.initials: P
authors.lastname: Park
authors.affiliation: Department of Biological Sciences and Brain and Cognitive Sciences, College of Natural Sciences, Seoul National University, Seoul 08826, Korea, Centre for Synaptic Plasticity, School of Physiology and Pharmacology, Bristol BS1 3NY, United Kingdom.
authors.forename: Thomas M
authors.identifier: http://orcid.org/0000-0003-2244-6591
authors.initials: TM
authors.lastname: Sanderson
authors.affiliation: Centre for Synaptic Plasticity, School of Physiology and Pharmacology, Bristol BS1 3NY, United Kingdom.
authors.forename: Mascia
authors.identifier: http://orcid.org/0000-0001-8548-4179
authors.initials: M
authors.lastname: Amici
authors.affiliation: Centre for Synaptic Plasticity, School of Physiology and Pharmacology, Bristol BS1 3NY, United Kingdom.
authors.forename: Sun-Lim
authors.initials: SL
authors.lastname: Choi
authors.affiliation: Centre for Synaptic Plasticity, School of Physiology and Pharmacology, Bristol BS1 3NY, United Kingdom.
authors.forename: Zuner A
authors.initials: ZA
authors.lastname: Bortolotto
authors.affiliation: Department of Biological Sciences and Brain and Cognitive Sciences, College of Natural Sciences, Seoul National University, Seoul 08826, Korea, Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Ontario M5S 1A8, Canada, and.
authors.forename: Min
authors.initials: M
authors.lastname: Zhuo
authors.affiliation: Department of Biological Sciences and Brain and Cognitive Sciences, College of Natural Sciences, Seoul National University, Seoul 08826, Korea, glcollingridge@gmail.com kaang@snu.ac.kr.
authors.forename: Bong-Kiun
authors.initials: BK
authors.lastname: Kaang
authors.affiliation: Department of Biological Sciences and Brain and Cognitive Sciences, College of Natural Sciences, Seoul National University, Seoul 08826, Korea, Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Ontario M5S 1A8, Canada, and Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada, and Centre for Synaptic Plasticity, School of Physiology and Pharmacology, Bristol BS1 3NY, United Kingdom glcollingridge@gmail.com kaang@snu.ac.kr.
authors.forename: Graham L
authors.identifier: http://orcid.org/0000-0002-9572-5359
authors.initials: GL
authors.lastname: Collingridge
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001703:Biophysics; D002118:Calcium / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D004558:Electric Stimulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists; D006624:Hippocampus / Q000166:cytology; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000502:physiology*; D018408:Patch-Clamp Techniques; D011073:Polyamines / Q000494:pharmacology; D051381:Rats; D018091:Receptors, AMPA / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020889:Rolipram / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; C110702:IEM 1460; D011073:Polyamines; D018091:Receptors, AMPA; C034092:delta-philanthotoxin; D017868:Cyclic AMP-Dependent Protein Kinases; D020889:Rolipram; D000218:Adamantane; D002118:Calcium
keywords: NMDA receptor; PKA; calcium-permeable AMPA receptor; hippocampus; long-term potentiation; rectification