title: AKAP150-anchored calcineurin regulates synaptic plasticity by limiting synaptic incorporation of Ca2+-permeable AMPA receptors.
abstract: AMPA receptors (AMPARs) are tetrameric ion channels assembled from GluA1-GluA4 subunits that mediate the majority of fast excitatory synaptic transmission in the brain. In the hippocampus, most synaptic AMPARs are composed of GluA1/2 or GluA2/3 with the GluA2 subunit preventing Ca(2+) influx. However, a small number of Ca(2+)-permeable GluA1 homomeric receptors reside in extrasynaptic locations where they can be rapidly recruited to synapses during synaptic plasticity. Phosphorylation of GluA1 S845 by the cAMP-dependent protein kinase (PKA) primes extrasynaptic receptors for synaptic insertion in response to NMDA receptor Ca(2+) signaling during long-term potentiation (LTP), while phosphatases dephosphorylate S845 and remove synaptic and extrasynaptic GluA1 during long-term depression (LTD). PKA and the Ca(2+)-activated phosphatase calcineurin (CaN) are targeted to GluA1 through binding to A-kinase anchoring protein 150 (AKAP150) in a complex with PSD-95, but we do not understand how the opposing activities of these enzymes are balanced to control plasticity. Here, we generated AKAP150ΔPIX knock-in mice to selectively disrupt CaN anchoring in vivo. We found that AKAP150ΔPIX mice lack LTD but express enhanced LTP at CA1 synapses. Accordingly, basal GluA1 S845 phosphorylation is elevated in AKAP150ΔPIX hippocampus, and LTD-induced dephosphorylation and removal of GluA1, AKAP150, and PSD-95 from synapses are impaired. In addition, basal synaptic activity of GluA2-lacking AMPARs is increased in AKAP150ΔPIX mice and pharmacologic antagonism of these receptors restores normal LTD and inhibits the enhanced LTP. Thus, AKAP150-anchored CaN opposes PKA phosphorylation of GluA1 to restrict synaptic incorporation of Ca(2+)-permeable AMPARs both basally and during LTP and LTD.
authors.affiliation: Department of Pharmacology, University of Colorado School of Medicine, Aurora, Colorado 80045, USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Sanderson
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Gorski
authors.forename: Emily S
authors.initials: ES
authors.lastname: Gibson
authors.forename: Philip
authors.initials: P
authors.lastname: Lam
authors.forename: Ronald K
authors.initials: RK
authors.lastname: Freund
authors.forename: Wallace S
authors.initials: WS
authors.lastname: Chick
authors.forename: Mark L
authors.initials: ML
authors.lastname: Dell'Acqua
mesh_terms: D054758:A Kinase Anchor Proteins / Q000235:genetics*; D000200:Action Potentials / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D001703:Biophysics; D019703:Calcineurin / Q000235:genetics / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D049229:Dendritic Spines / Q000648:ultrastructure; D000076122:Disks Large Homolog 4 Protein; D004558:Electric Stimulation; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D005260:Female; D051528:Guanylate Kinases / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology; D047468:Immunoprecipitation; D066298:In Vitro Techniques; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D016202:N-Methylaspartate / Q000494:pharmacology; D009473:Neuronal Plasticity / Q000235:genetics / Q000502:physiology*; D009474:Neurons / Q000648:ultrastructure; D018408:Patch-Clamp Techniques; D010766:Phosphorylation; D011810:Quinoxalines / Q000494:pharmacology; D018091:Receptors, AMPA / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D016622:Silver Staining; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013347:Subcellular Fractions / Q000378:metabolism / Q000648:ultrastructure; D013569:Synapses / Q000502:physiology* / Q000648:ultrastructure; D013779:Tetrodotoxin / Q000494:pharmacology
chemical_list: D054758:A Kinase Anchor Proteins; C520665:Akap5 protein, mouse; D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D008565:Membrane Proteins; D011810:Quinoxalines; D018091:Receptors, AMPA; D026941:Sodium Channel Blockers; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; D013779:Tetrodotoxin; D012694:Serine; D016202:N-Methylaspartate; D051528:Guanylate Kinases; D019703:Calcineurin; D002118:Calcium