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.

Epilepsy and intellectual disability linked protein Shrm4 interaction with GABABRs shapes inhibitory neurotransmission / J. Zapata, E. Moretto, S. Hannan, L. Murru, A. Longatti, D. Mazza, L. Benedetti, M. Fossati, C. Heise, L. Ponzoni, P. Valnegri, D. Braida, M. Sala, M. Francolini, J. Hildebrand, V. Kalscheuer, F. Fanelli, C. Sala, B. Bettler, S. Bassani, T.G. Smart, M. Passafaro. - In: NATURE COMMUNICATIONS. - ISSN 2041-1723. - 8(2017), pp. 14536.1-14536.17. [10.1038/ncomms14536]

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

J. Zapata
Primo
;
E. Moretto
Secondo
;
A. Longatti;L. Benedetti;M. Fossati;C. Heise;L. Ponzoni;P. Valnegri;D. Braida;M. Sala;M. Francolini;S. Bassani;
2017

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.
GABA(A) receptor trafficking; autism spectrum disorders; mice lacking GABA(B(1)); dendritic spines; dentate gyrus; sushi domains; susceptibility; localization; subunit; delta
Settore BIO/14 - Farmacologia
2017
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/522647
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