Depdc5 knockdown causes mTOR-dependent motor hyperactivity in zebrafish

Annals of Clinical and Translational Neurology
Hortense de CalbiacSorana Ciura

Abstract

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 the...Continue Reading

References

Jul 1, 1995·Developmental Dynamics : an Official Publication of the American Association of Anatomists·C B KimmelT F Schilling
Nov 27, 2002·Progress in Neurobiology·Pierre DrapeauEdna Brustein
Apr 12, 2008·Development·Judith S Eisen, James C Smith
Mar 10, 2010·Disease Models & Mechanisms·Gabriela A HortopanScott C Baraban
Apr 2, 2013·Nature Genetics·Leanne M DibbensIngrid E Scheffer
Apr 2, 2013·Nature Genetics·Saeko IshidaStéphanie Baulac
Sep 5, 2013·Nature Communications·Scott C BarabanGabriela A Hortopan
Nov 12, 2013·American Journal of Human Genetics·Arvid SulsUNKNOWN EuroEPINOMICS RES Consortium
Jan 28, 2015·Annals of Neurology·Stéphanie BaulacFabienne Picard
Feb 25, 2015·Nature Neuroscience·Brian P Grone, Scott C Baraban
Apr 3, 2015·Cold Spring Harbor Perspectives in Medicine·Peter B Crino
May 23, 2015·Annals of Clinical and Translational Neurology·Thomas ScerriRichard J Leventer
Jul 15, 2015·Nature·Andrea RossiDidier Y R Stainier
Jan 21, 2016·Epilepsia·Georg-Christoph KorenkeOrtrud K Steinlein
Feb 14, 2016·Neurobiology of Disease·Elise MarsanStéphanie Baulac
Sep 11, 2017·Neurobiology of Disease·Chloë ScheldemanPeter A M de Witte
Oct 20, 2017·PLoS Genetics·Didier Y R StainierCecilia B Moens

❮ Previous
Next ❯

Citations

Oct 21, 2020·Nature Reviews. Neurology·Rima Nabbout, Mathieu Kuchenbuch
May 8, 2020·Neurobiology of Disease·Annis-Rayan BourefisEdor Kabashi
Jun 17, 2020·Neuroscience and Biobehavioral Reviews·Kinga GawelCamila V Esguerra
Apr 27, 2021·Frontiers in Neuroanatomy·Lena H Nguyen, Angélique Bordey
Jul 27, 2021·Neuroscience Bulletin·Tiantian WangGang Peng
Oct 2, 2021·Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics·Aleksandr Shcheglovitov, Randall T Peterson

❮ Previous
Next ❯

Datasets Mentioned

BETA
BC144291

Methods Mentioned

BETA
PCR

Software Mentioned

Excel
ImageJ
SigmaStat
Clampfit

Related Concepts

Related Feeds

Attention Disorders

Attention is involved in all cognitive activities, and attention disorders are reported in patients with various neurological diseases. Here are the latest discoveries pertaining to attention disorders.