title: Network compensation of cyclic GMP-dependent protein kinase II knockout in the hippocampus by Ca2+-permeable AMPA receptors.
abstract: Gene knockout (KO) does not always result in phenotypic changes, possibly due to mechanisms of functional compensation. We have studied mice lacking cGMP-dependent kinase II (cGKII), which phosphorylates GluA1, a subunit of AMPA receptors (AMPARs), and promotes hippocampal long-term potentiation (LTP) through AMPAR trafficking. Acute cGKII inhibition significantly reduces LTP, whereas cGKII KO mice show no LTP impairment. Significantly, the closely related kinase, cGKI, does not compensate for cGKII KO. Here, we describe a previously unidentified pathway in the KO hippocampus that provides functional compensation for the LTP impairment observed when cGKII is acutely inhibited. We found that in cultured cGKII KO hippocampal neurons, cGKII-dependent phosphorylation of inositol 1,4,5-trisphosphate receptors was decreased, reducing cytoplasmic Ca(2+) signals. This led to a reduction of calcineurin activity, thereby stabilizing GluA1 phosphorylation and promoting synaptic expression of Ca(2+)-permeable AMPARs, which in turn induced a previously unidentified form of LTP as a compensatory response in the KO hippocampus. Calcineurin-dependent Ca(2+)-permeable AMPAR expression observed here is also used during activity-dependent homeostatic synaptic plasticity. Thus, a homeostatic mechanism used during activity reduction provides functional compensation for gene KO in the cGKII KO hippocampus.
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016;
authors.forename: Seonil
authors.initials: S
authors.lastname: Kim
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016;
authors.forename: Roseann F
authors.initials: RF
authors.lastname: Titcombe
authors.affiliation: Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY 10032; and.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016;
authors.forename: Latika
authors.initials: L
authors.lastname: Khatri
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016;
authors.forename: Hiwot K
authors.initials: HK
authors.lastname: Girma
authors.affiliation: Technical University of Munich, 80802 Munich, Germany.
authors.forename: Franz
authors.initials: F
authors.lastname: Hofmann
authors.affiliation: Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY 10032; and.
authors.forename: Ottavio
authors.initials: O
authors.lastname: Arancio
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016; edward.ziff@nyumc.org.
authors.forename: Edward B
authors.initials: EB
authors.lastname: Ziff
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D062967:Cyclic GMP-Dependent Protein Kinase Type II / Q000235:genetics / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology* / Q000502:physiology; D006706:Homeostasis / Q000187:drug effects; D017774:Long-Term Potentiation; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D018091:Receptors, AMPA / Q000378:metabolism*; D013569:Synapses / Q000201:enzymology / Q000378:metabolism; D013779:Tetrodotoxin / Q000494:pharmacology
chemical_list: D018091:Receptors, AMPA; D013779:Tetrodotoxin; D062967:Cyclic GMP-Dependent Protein Kinase Type II; D002118:Calcium
keywords: Ca2+-permeable AMPA receptors; LTP; calcineurin; gene knockout