title: Epilepsy and intellectual disability linked protein Shrm4 interaction with GABABRs shapes inhibitory neurotransmission.
abstract: Shrm4, a protein expressed only in polarized tissues, is encoded by the KIAA1202 gene, whose mutations have been linked to epilepsy and intellectual disability. However, a physiological role for Shrm4 in the brain is yet to be established. Here, we report that Shrm4 is localized to synapses where it regulates dendritic spine morphology and interacts with the C terminus of GABABreceptors (GABABRs) to control their cell surface expression and intracellular trafficking via a dynein-dependent mechanism. Knockdown of Shrm4 in rat severely impairs GABABR activity causing increased anxiety-like behaviour and susceptibility to seizures. Moreover, Shrm4 influences hippocampal excitability by modulating tonic inhibition in dentate gyrus granule cells, in a process involving crosstalk between GABABRs and extrasynaptic δ-subunit-containing GABAARs. Our data highlights a role for Shrm4 in synaptogenesis and in maintaining GABABR-mediated inhibition, perturbation of which may be responsible for the involvement of Shrm4 in cognitive disorders and epilepsy.
authors.affiliation: CNR, Institute of Neuroscience, Via Vanvitelli, 32, 20129 Milano, Italy.|Department of Medical Biotechnology and Translational Medicine (BIOMETRA), Università di Milano, Via Vanvitelli, 32, 20129 Milano, Italy.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Zapata
authors.affiliation: CNR, Institute of Neuroscience, Via Vanvitelli, 32, 20129 Milano, Italy.|Department of Medical Biotechnology and Translational Medicine (BIOMETRA), Università di Milano, Via Vanvitelli, 32, 20129 Milano, Italy.
authors.forename: Edoardo
authors.initials: E
authors.lastname: Moretto
authors.affiliation: Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London WC1E 6BT, UK.
authors.forename: Saad
authors.identifier: 0000-0003-4594-0808
authors.initials: S
authors.lastname: Hannan
authors.affiliation: CNR, Institute of Neuroscience, Via Vanvitelli, 32, 20129 Milano, Italy.|Department of Medical Biotechnology and Translational Medicine (BIOMETRA), Università di Milano, Via Vanvitelli, 32, 20129 Milano, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Murru
authors.affiliation: CNR, Institute of Neuroscience, Via Vanvitelli, 32, 20129 Milano, Italy.|Department of Pharmacological and Biomolecular Sciences (DiSFeB)-Università di Milano, Via Balzaretti 9, 20133 Milano, Italy.
authors.forename: Anna
authors.identifier: 0000-0002-1636-8550
authors.initials: A
authors.lastname: Longatti
authors.affiliation: Centro di Imaging Sperimentale e Università Vita-Salute San Raffaele, Istituto Scientifico Ospedale San Raffaele, Via Olgettina 60, Milano 20132, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Mazza
authors.affiliation: CNR, Institute of Neuroscience, Via Vanvitelli, 32, 20129 Milano, Italy.|Department of Medical Biotechnology and Translational Medicine (BIOMETRA), Università di Milano, Via Vanvitelli, 32, 20129 Milano, Italy.
authors.forename: Lorena
authors.initials: L
authors.lastname: Benedetti
authors.affiliation: CNR, Institute of Neuroscience, Via Vanvitelli, 32, 20129 Milano, Italy.|Department of Medical Biotechnology and Translational Medicine (BIOMETRA), Università di Milano, Via Vanvitelli, 32, 20129 Milano, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Fossati
authors.affiliation: CNR, Institute of Neuroscience, Via Vanvitelli, 32, 20129 Milano, Italy.|Department of Medical Biotechnology and Translational Medicine (BIOMETRA), Università di Milano, Via Vanvitelli, 32, 20129 Milano, Italy.
authors.forename: Christopher
authors.initials: C
authors.lastname: Heise
authors.affiliation: Fondazione Umberto Veronesi, Piazza Velasca 5, Milan 20122, Italy.
authors.forename: Luisa
authors.initials: L
authors.lastname: Ponzoni
authors.affiliation: CNR, Institute of Neuroscience, Via Vanvitelli, 32, 20129 Milano, Italy.|Department of Medical Biotechnology and Translational Medicine (BIOMETRA), Università di Milano, Via Vanvitelli, 32, 20129 Milano, Italy.
authors.forename: Pamela
authors.initials: P
authors.lastname: Valnegri
authors.affiliation: Department of Medical Biotechnology and Translational Medicine (BIOMETRA), Università di Milano, Via Vanvitelli, 32, 20129 Milano, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Braida
authors.affiliation: CNR, Institute of Neuroscience, Via Vanvitelli, 32, 20129 Milano, Italy.|Department of Medical Biotechnology and Translational Medicine (BIOMETRA), Università di Milano, Via Vanvitelli, 32, 20129 Milano, Italy.
authors.forename: Mariaelvina
authors.identifier: 0000-0001-9310-958X
authors.initials: M
authors.lastname: Sala
authors.affiliation: CNR, Institute of Neuroscience, Via Vanvitelli, 32, 20129 Milano, Italy.|Department of Medical Biotechnology and Translational Medicine (BIOMETRA), Università di Milano, Via Vanvitelli, 32, 20129 Milano, Italy.
authors.forename: Maura
authors.initials: M
authors.lastname: Francolini
authors.affiliation: Department of Biological Sciences, University of Pittsburgh, 103A Life Sciences Annex 4249, Fifth Avenue Pittsburgh, Pennsylvania 15260, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Hildebrand
authors.affiliation: Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics, Ihnestrasse 63-73, D-14195 Berlin, Germany.
authors.forename: Vera
authors.initials: V
authors.lastname: Kalscheuer
authors.affiliation: Department of Life Sciences, University of Modena and Reggio Emilia, via Campi 103, 41125 Modena, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Fanelli
authors.affiliation: CNR, Institute of Neuroscience, Via Vanvitelli, 32, 20129 Milano, Italy.|Department of Medical Biotechnology and Translational Medicine (BIOMETRA), Università di Milano, Via Vanvitelli, 32, 20129 Milano, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Sala
authors.affiliation: Department of Biomedicine, University of Basel, Klingelbergstrasse 50/70, CH-4056 Basel, Switzerland.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Bettler
authors.affiliation: CNR, Institute of Neuroscience, Via Vanvitelli, 32, 20129 Milano, Italy.|Department of Medical Biotechnology and Translational Medicine (BIOMETRA), Università di Milano, Via Vanvitelli, 32, 20129 Milano, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Bassani
authors.affiliation: Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London WC1E 6BT, UK.
authors.forename: Trevor G
authors.initials: TG
authors.lastname: Smart
authors.affiliation: CNR, Institute of Neuroscience, Via Vanvitelli, 32, 20129 Milano, Italy.|Department of Medical Biotechnology and Translational Medicine (BIOMETRA), Università di Milano, Via Vanvitelli, 32, 20129 Milano, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Passafaro
mesh_terms: D000818:Animals; D018891:Dentate Gyrus / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D004622:Embryo, Mammalian; D004827:Epilepsy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D006801:Humans; D007276:Injections, Intraventricular; D008607:Intellectual Disability / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008840:Microfilament Proteins / Q000235:genetics* / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009433:Neural Inhibition; D055495:Neurogenesis / Q000235:genetics; D009474:Neurons / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D061251:Primary Cell Culture; D051381:Rats; D017208:Rats, Wistar; D020239:Receptor Cross-Talk; D011963:Receptors, GABA-A / Q000235:genetics* / Q000378:metabolism; D018080:Receptors, GABA-B / Q000235:genetics* / Q000378:metabolism; D013569:Synapses / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D009435:Synaptic Transmission / Q000235:genetics*
chemical_list: D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; D011963:Receptors, GABA-A; D018080:Receptors, GABA-B