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Complex regulation of Gephyrin splicing is a determinant of inhibitory postsynaptic diversity

Raphaël Dos Reis, Etienne Kornobis, Alyssa Pereira, Frederic Tores, Judit Carrasco, Candice Gautier, Céline Jahannault-Talignani, Patrick Nitschké, Christian Muchardt, Andreas Schlosser, Hans Michael Maric, Fabrice Ango (fabrice.ango@inserm.fr) and Eric Allemand (eric.allemand@inserm.fr)
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Raphaël Dos Reis: INM, Université Montpellier, CNRS, INSERM
Etienne Kornobis: C2RT, Institut Pasteur
Alyssa Pereira: INM, Université Montpellier, CNRS, INSERM
Frederic Tores: BIP-D Plateforme de Bioinformatique Paris-Descartes, Institut Imagine
Judit Carrasco: UMR 3738, Unité de Régulation Épigénétique, Institut Pasteur
Candice Gautier: Institut Imagine, INSERM - U1163, Unité mécanismes cellulaires et moléculaires des désordres hématologiques et implications thérapeutiques
Céline Jahannault-Talignani: INM, Université Montpellier, CNRS, INSERM
Patrick Nitschké: BIP-D Plateforme de Bioinformatique Paris-Descartes, Institut Imagine
Christian Muchardt: UMR 3738, Unité de Régulation Épigénétique, Institut Pasteur
Andreas Schlosser: University of Würzburg
Hans Michael Maric: University of Würzburg, Biotechnology and Biophysics, Rudolf Virchow Zentrum Gebäude D15
Fabrice Ango: INM, Université Montpellier, CNRS, INSERM
Eric Allemand: UMR 3738, Unité de Régulation Épigénétique, Institut Pasteur

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: Abstract Gephyrin (GPHN) regulates the clustering of postsynaptic components at inhibitory synapses and is involved in pathophysiology of neuropsychiatric disorders. Here, we uncover an extensive diversity of GPHN transcripts that are tightly controlled by splicing during mouse and human brain development. Proteomic analysis reveals at least a hundred isoforms of GPHN incorporated at inhibitory Glycine and gamma-aminobutyric acid A receptors containing synapses. They exhibit different localization and postsynaptic clustering properties, and altering the expression level of one isoform is sufficient to affect the number, size, and density of inhibitory synapses in cerebellar Purkinje cells. Furthermore, we discovered that splicing defects reported in neuropsychiatric disorders are carried by multiple alternative GPHN transcripts, demonstrating the need for a thorough analysis of the GPHN transcriptome in patients. Overall, we show that alternative splicing of GPHN is an important genetic variation to consider in neurological diseases and a determinant of the diversity of postsynaptic inhibitory synapses.

Date: 2022
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DOI: 10.1038/s41467-022-31264-w

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