Epilepsy and intellectual disability linked protein Shrm4 interaction with GABABRs shapes inhibitory neurotransmission

Jonathan Zapata, Edoardo Moretto, Saad Hannan, Luca Murru, Anna Longatti, Davide Mazza, Lorena Benedetti, Matteo Fossati, Christopher Heise, Luisa Ponzoni, Pamela Valnegri, Daniela Braida, Mariaelvina Sala, Maura Francolini, Jeffrey Hildebrand, Vera Kalscheuer, Francesca Fanelli, Carlo Sala, Bernhard Bettler, Silvia Bassani, Trevor G. Smart and Maria Passafaro ()
Additional contact information
Jonathan Zapata: CNR, Institute of Neuroscience
Edoardo Moretto: CNR, Institute of Neuroscience
Saad Hannan: Physiology and Pharmacology, University College London
Luca Murru: CNR, Institute of Neuroscience
Anna Longatti: CNR, Institute of Neuroscience
Davide Mazza: Centro di Imaging Sperimentale e Università Vita-Salute San Raffaele, Istituto Scientifico Ospedale San Raffaele, Via Olgettina 60
Lorena Benedetti: CNR, Institute of Neuroscience
Matteo Fossati: CNR, Institute of Neuroscience
Christopher Heise: CNR, Institute of Neuroscience
Luisa Ponzoni: Fondazione Umberto Veronesi, Piazza Velasca 5
Pamela Valnegri: CNR, Institute of Neuroscience
Daniela Braida: Università di Milano
Mariaelvina Sala: CNR, Institute of Neuroscience
Maura Francolini: CNR, Institute of Neuroscience
Jeffrey Hildebrand: University of Pittsburgh
Vera Kalscheuer: Max Planck Institute for Molecular Genetics
Francesca Fanelli: University of Modena and Reggio Emilia
Carlo Sala: CNR, Institute of Neuroscience
Bernhard Bettler: University of Basel
Silvia Bassani: CNR, Institute of Neuroscience
Trevor G. Smart: Physiology and Pharmacology, University College London
Maria Passafaro: CNR, Institute of Neuroscience

Nature Communications, 2017, vol. 8, issue 1, 1-17

Abstract: 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 GABAB receptors (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.

Date: 2017
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DOI: 10.1038/ncomms14536

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