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Ann Clin Transl Neurol. 2018 Apr 6;5(5):510-523. doi: 10.1002/acn3.542. eCollection 2018 May.

Depdc5 knockdown causes mTOR-dependent motor hyperactivity in zebrafish.

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Sorbonne Universités Paris VI UMR CNRS 1127 UPMC INSERM U 1127 CNRS UMR 7225 Institut du Cerveau et de la Moelle épinière - ICM Paris France.
Institut Imagine UMR Inserm 1163 University Paris Descartes Hospital Necker-Enfants Malades 24 Boulevard du Montparnasse Paris 75015 France.
Transylvanian Institute of Neuroscience (TINS) Str. Ploiesti 33 Cluj-Napoca 400157 Romania.
Evolution des Régulations Endocriniennes UMR 7221 CNRS and Muséum National d'Histoire Naturelle Paris France.



DEPDC5 was identified as a major genetic cause of focal epilepsy with deleterious mutations found in a wide range of inherited forms of focal epilepsy, associated with malformation of cortical development in certain cases. Identification of frameshift, truncation, and deletion mutations implicates haploinsufficiency of DEPDC5 in the etiology of focal epilepsy. DEPDC5 is a component of the GATOR1 complex, acting as a negative regulator of mTOR signaling.


Zebrafish represents a vertebrate model suitable for genetic analysis and drug screening in epilepsy-related disorders. In this study, we defined the expression of depdc5 during development and established an epilepsy model with reduced Depdc5 expression.


Here we report a zebrafish model of Depdc5 loss-of-function that displays a measurable behavioral phenotype, including hyperkinesia, circular swimming, and increased neuronal activity. These phenotypic features persisted throughout embryonic development and were significantly reduced upon treatment with the mTORC1 inhibitor, rapamycin, as well as overexpression of human WT DEPDC5 transcript. No phenotypic rescue was obtained upon expression of epilepsy-associated DEPDC5 mutations (p.Arg487* and p.Arg485Gln), indicating that these mutations cause a loss of function of the protein.


This study demonstrates that Depdc5 knockdown leads to early-onset phenotypic features related to motor and neuronal hyperactivity. Restoration of phenotypic features by WT but not epilepsy-associated Depdc5 mutants, as well as by mTORC1 inhibition confirm the role of Depdc5 in the mTORC1-dependent molecular cascades, defining this pathway as a potential therapeutic target for DEPDC5-inherited forms of focal epilepsy.

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