title: A SLM2 Feedback Pathway Controls Cortical Network Activity and Mouse Behavior.
abstract: The brain is made up of trillions of synaptic connections that together form neural networks needed for normal brain function and behavior. SLM2 is a member of a conserved family of RNA binding proteins, including Sam68 and SLM1, that control splicing of Neurexin1-3 pre-mRNAs. Whether SLM2 affects neural network activity is unknown. Here, we find that SLM2 levels are maintained by a homeostatic feedback control pathway that predates the divergence of SLM2 and Sam68. SLM2 also controls the splicing of Tomosyn2, LysoPLD/ATX, Dgkb, Kif21a, and Cask, each of which are important for synapse function. Cortical neural network activity dependent on synaptic connections between SLM2-expressing-pyramidal neurons and interneurons is decreased in Slm2-null mice. Additionally, these mice are anxious and have a decreased ability to recognize novel objects. Our data reveal a pathway of SLM2 homeostatic auto-regulation controlling brain network activity and behavior.
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Ehrmann
authors.affiliation: Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Gazzara
authors.affiliation: Department of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Rome and Laboratory of Neuroembryology, Fondazione Santa Lucia, 00143 Rome, Italy.
authors.forename: Vittoria
authors.initials: V
authors.lastname: Pagliarini
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.
authors.forename: Caroline
authors.initials: C
authors.lastname: Dalgliesh
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.
authors.forename: Mahsa
authors.initials: M
authors.lastname: Kheirollahi-Chadegani
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.
authors.forename: Yaobo
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Rome and Laboratory of Neuroembryology, Fondazione Santa Lucia, 00143 Rome, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Cesari
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.
authors.forename: Marina
authors.initials: M
authors.lastname: Danilenko
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.
authors.forename: Marie
authors.initials: M
authors.lastname: Maclennan
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.
authors.forename: Kate
authors.initials: K
authors.lastname: Lowdon
authors.affiliation: Department of Molecular Embryology, Institute of Anatomy and Cell Biology, Medical Faculty, University of Freiburg, 79104 Freiburg, Germany.
authors.forename: Tanja
authors.initials: T
authors.lastname: Vogel
authors.affiliation: Mary Lyon Centre, MRC Harwell Institute, Oxfordshire OX11 ORD, UK.
authors.forename: Piia
authors.initials: P
authors.lastname: Keskivali-Bond
authors.affiliation: Mary Lyon Centre, MRC Harwell Institute, Oxfordshire OX11 ORD, UK.
authors.forename: Sara
authors.initials: S
authors.lastname: Wells
authors.affiliation: Mary Lyon Centre, MRC Harwell Institute, Oxfordshire OX11 ORD, UK.
authors.forename: Heather
authors.initials: H
authors.lastname: Cater
authors.affiliation: Université Montpellier, UMR 5237, Centre de Recherche de Biologie cellulaire de Montpellier, CNRS, Montpellier 34293, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Fort
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.
authors.forename: Mauro
authors.initials: M
authors.lastname: Santibanez-Koref
authors.affiliation: Institute of Cell Biology and Neurobiology, Consiglio Nazionale delle Ricerche, Via E. Ramarini 32, 00015 Monterotondo Scalo-Roma, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Middei
authors.affiliation: Department of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Rome and Laboratory of Neuroembryology, Fondazione Santa Lucia, 00143 Rome, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Sette
authors.affiliation: Institute of Neuroscience, Newcastle University, Newcastle upon Tyne NE1 7RU, UK. Electronic address: gavin.clowry@ncl.ac.uk.
authors.forename: Gavin J
authors.initials: GJ
authors.lastname: Clowry
authors.affiliation: Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Computer and Information Science, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: yosephb@upenn.edu.
authors.forename: Yoseph
authors.initials: Y
authors.lastname: Barash
authors.affiliation: Institute of Neuroscience, Newcastle University, Newcastle upon Tyne NE1 7RU, UK. Electronic address: mark.cunningham@ncl.ac.uk.
authors.forename: Mark O
authors.initials: MO
authors.lastname: Cunningham
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK. Electronic address: david.elliott@newcastle.ac.uk.
authors.forename: David J
authors.initials: DJ
authors.lastname: Elliott
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D017398:Alternative Splicing / Q000235:genetics*; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D002135:Calcium-Binding Proteins; D006706:Homeostasis / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009415:Nerve Net; D019006:Neural Cell Adhesion Molecules / Q000235:genetics; D017966:Pyramidal Cells / Q000378:metabolism*; D012322:RNA Precursors / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D013569:Synapses / Q000235:genetics* / Q000502:physiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002135:Calcium-Binding Proteins; C513253:Khdrbs1 protein, mouse; C118776:Khdrbs2 protein, mouse; C486528:Khdrbs3 protein, mouse; D019006:Neural Cell Adhesion Molecules; C527193:Nrxn1 protein, mouse; D012322:RNA Precursors; D016601:RNA-Binding Proteins
keywords: Neurexin splicing; RNA binding proteins; RNA-seq; alternative splicing; brain; gene expression; hippocampus; neuron; transcriptome