title: NMDA Receptor-Dependent LTD Requires Transient Synaptic Incorporation of Ca²⁺-Permeable AMPARs Mediated by AKAP150-Anchored PKA and Calcineurin.
abstract: Information processing in the brain requires multiple forms of synaptic plasticity that converge on regulation of NMDA and AMPA-type glutamate receptors (NMDAR, AMPAR), including long-term potentiation (LTP) and long-term depression (LTD) and homeostatic scaling. In some cases, LTP and homeostatic plasticity regulate synaptic AMPAR subunit composition to increase the contribution of Ca(2+)-permeable receptors (CP-AMPARs) containing GluA1 but lacking GluA2 subunits. Here, we show that PKA anchored to the scaffold protein AKAP150 regulates GluA1 phosphorylation and plays a novel role controlling CP-AMPAR synaptic incorporation during NMDAR-dependent LTD. Using knockin mice that are deficient in AKAP-anchoring of either PKA or the opposing phosphatase calcineurin, we found that CP-AMPARs are recruited to hippocampal synapses by anchored PKA during LTD induction but are then rapidly removed by anchored calcineurin. Importantly, blocking CP-AMPAR recruitment, removal, or activity interferes with LTD. Thus, CP-AMPAR synaptic recruitment is required to transiently augment NMDAR Ca(2+) signaling during LTD induction.
authors.affiliation: Department of Pharmacology, University of Colorado School of Medicine, 12800 East 19th Avenue, Aurora, CO 80045, USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Sanderson
authors.affiliation: Department of Pharmacology, University of Colorado School of Medicine, 12800 East 19th Avenue, Aurora, CO 80045, USA.
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Gorski
authors.affiliation: Department of Pharmacology, University of Colorado School of Medicine, 12800 East 19th Avenue, Aurora, CO 80045, USA; Program in Neuroscience, University of Colorado School of Medicine, 12800 East 19th Avenue, Aurora, CO 80045, USA. Electronic address: mark.dellacqua@ucdenver.edu.
authors.forename: Mark L
authors.initials: ML
authors.lastname: Dell'Acqua
mesh_terms: D054758:A Kinase Anchor Proteins / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D019703:Calcineurin / Q000235:genetics / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D004558:Electric Stimulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018683:Excitatory Amino Acid Agents / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology / Q000648:ultrastructure; D036881:Long-Term Synaptic Depression / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008958:Models, Molecular; D009154:Mutation / Q000235:genetics; D018091:Receptors, AMPA / Q000235:genetics / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*; D016622:Silver Staining; D013569:Synapses / Q000235:genetics / Q000502:physiology* / Q000648:ultrastructure; D055366:Synaptic Potentials / Q000187:drug effects / Q000235:genetics
chemical_list: D054758:A Kinase Anchor Proteins; C520665:Akap5 protein, mouse; D004791:Enzyme Inhibitors; D018683:Excitatory Amino Acid Agents; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D017868:Cyclic AMP-Dependent Protein Kinases; D019703:Calcineurin; D002118:Calcium