title: PRG-1 Regulates Synaptic Plasticity via Intracellular PP2A/β1-Integrin Signaling.
abstract: Alterations in dendritic spine numbers are linked to deficits in learning and memory. While we previously revealed that postsynaptic plasticity-related gene 1 (PRG-1) controls lysophosphatidic acid (LPA) signaling at glutamatergic synapses via presynaptic LPA receptors, we now show that PRG-1 also affects spine density and synaptic plasticity in a cell-autonomous fashion via protein phosphatase 2A (PP2A)/β1-integrin activation. PRG-1 deficiency reduces spine numbers and β1-integrin activation, alters long-term potentiation (LTP), and impairs spatial memory. The intracellular PRG-1 C terminus interacts in an LPA-dependent fashion with PP2A, thus modulating its phosphatase activity at the postsynaptic density. This results in recruitment of adhesome components src, paxillin, and talin to lipid rafts and ultimately in activation of β1-integrins. Consistent with these findings, activation of PP2A with FTY720 rescues defects in spine density and LTP of PRG-1-deficient animals. These results disclose a mechanism by which bioactive lipid signaling via PRG-1 could affect synaptic plasticity and memory formation.
authors.affiliation: Institute of Microanatomy and Neurobiology, University Medical Center, Langenbeckstrasse 1, 55131 Mainz, Germany.
authors.forename: Xingfeng
authors.initials: X
authors.lastname: Liu
authors.affiliation: Institute of Microanatomy and Neurobiology, University Medical Center, Langenbeckstrasse 1, 55131 Mainz, Germany. Electronic address: jisen.huai@unimedizin-mainz.de.
authors.forename: Jisen
authors.initials: J
authors.lastname: Huai
authors.affiliation: Institute of Microanatomy and Neurobiology, University Medical Center, Langenbeckstrasse 1, 55131 Mainz, Germany.
authors.forename: Heiko
authors.initials: H
authors.lastname: Endle
authors.affiliation: Institute of Microanatomy and Neurobiology, University Medical Center, Langenbeckstrasse 1, 55131 Mainz, Germany.
authors.forename: Leslie
authors.initials: L
authors.lastname: Schlüter
authors.affiliation: Institute of Microanatomy and Neurobiology, University Medical Center, Langenbeckstrasse 1, 55131 Mainz, Germany.
authors.forename: Wei
authors.initials: W
authors.lastname: Fan
authors.affiliation: Institute of Microanatomy and Neurobiology, University Medical Center, Langenbeckstrasse 1, 55131 Mainz, Germany.
authors.forename: Yunbo
authors.initials: Y
authors.lastname: Li
authors.affiliation: Institute of Microanatomy and Neurobiology, University Medical Center, Langenbeckstrasse 1, 55131 Mainz, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Richers
authors.affiliation: MSU-FZI, Institute for Immunology, University Medical Center, Langenbeckstrasse 1, 55131 Mainz, Germany.
authors.forename: Hajime
authors.initials: H
authors.lastname: Yurugi
authors.affiliation: MSU-FZI, Institute for Immunology, University Medical Center, Langenbeckstrasse 1, 55131 Mainz, Germany.
authors.forename: Krishnaraj
authors.initials: K
authors.lastname: Rajalingam
authors.affiliation: Institute of Microanatomy and Neurobiology, University Medical Center, Langenbeckstrasse 1, 55131 Mainz, Germany.
authors.forename: Haichao
authors.initials: H
authors.lastname: Ji
authors.affiliation: Institute of Microanatomy and Neurobiology, University Medical Center, Langenbeckstrasse 1, 55131 Mainz, Germany.
authors.forename: Hong
authors.initials: H
authors.lastname: Cheng
authors.affiliation: Institute of Microanatomy and Neurobiology, University Medical Center, Langenbeckstrasse 1, 55131 Mainz, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Rister
authors.affiliation: Institute of Microanatomy and Neurobiology, University Medical Center, Langenbeckstrasse 1, 55131 Mainz, Germany.
authors.forename: Guilherme
authors.initials: G
authors.lastname: Horta
authors.affiliation: Institute of Microanatomy and Neurobiology, University Medical Center, Langenbeckstrasse 1, 55131 Mainz, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Baumgart
authors.affiliation: Institute of Microanatomy and Neurobiology, University Medical Center, Langenbeckstrasse 1, 55131 Mainz, Germany.
authors.forename: Hendrik
authors.initials: H
authors.lastname: Berger
authors.affiliation: Institute for Integrative Neuroanatomy, CCO, Charité - University Medicine Berlin, Charitéplatz 1, 10117 Berlin, Germany.
authors.forename: Gregor
authors.initials: G
authors.lastname: Laube
authors.affiliation: Department for Psychiatry and Psychotherapy, University Medical Center, Untere Zahlbacher Street 8, 55131 Mainz, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Schmitt
authors.affiliation: Institute for Anatomy and Cell Biology, Ulm University, Albert-Einstein-Allee 11, 89081 Ulm, Germany; Department of Neurology, Ulm University, Oberer Eselsberg 45, 89081 Ulm, Germany.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Schmeisser
authors.affiliation: Institute for Anatomy and Cell Biology, Ulm University, Albert-Einstein-Allee 11, 89081 Ulm, Germany.
authors.forename: Tobias M
authors.initials: TM
authors.lastname: Boeckers
authors.affiliation: MSU-FZI, Institute for Immunology, University Medical Center, Langenbeckstrasse 1, 55131 Mainz, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Tenzer
authors.affiliation: Institute for Clinical Neuroanatomy, Neuroscience Center, Goethe University Frankfurt, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Vlachos
authors.affiliation: Institute for Clinical Neuroanatomy, Neuroscience Center, Goethe University Frankfurt, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Deller
authors.affiliation: Institute of Microanatomy and Neurobiology, University Medical Center, Langenbeckstrasse 1, 55131 Mainz, Germany. Electronic address: robert.nitsch@unimedizin-mainz.de.
authors.forename: Robert
authors.initials: R
authors.lastname: Nitsch
authors.affiliation: Institute of Microanatomy and Neurobiology, University Medical Center, Langenbeckstrasse 1, 55131 Mainz, Germany. Electronic address: johannes.vogt@unimedizin-mainz.de.
authors.forename: Johannes
authors.initials: J
authors.lastname: Vogt
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D049229:Dendritic Spines / Q000235:genetics / Q000378:metabolism*; D022001:Focal Adhesions / Q000502:physiology; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D019012:Integrin beta1 / Q000235:genetics / Q000378:metabolism*; D017774:Long-Term Potentiation; D008246:Lysophospholipids / Q000378:metabolism*; D021962:Membrane Microdomains / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009473:Neuronal Plasticity / Q000502:physiology*; D054648:Protein Phosphatase 2 / Q000235:genetics / Q000378:metabolism*; D064067:Rho Guanine Nucleotide Exchange Factors; D015398:Signal Transduction; D013569:Synapses / Q000502:physiology*
chemical_list: C574809:ARHGEF11 protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D019012:Integrin beta1; D008246:Lysophospholipids; D064067:Rho Guanine Nucleotide Exchange Factors; D054648:Protein Phosphatase 2; C032881:lysophosphatidic acid