TBC1D24, responsible for early-onset epilepsies associated with intellectual disabilities, plays a role in the formation and maturation of cerebral cortex. A. Falace1,5, E. Buhler3, M. Fadda5,6, F. Watrin1,2, P. Lippiello5, E. Pallesi-Pocachard4, P. Baldelli5,6, F. Benfenati5,6, F. Zara7, A. Represa1,2, A. Fassio5,6, C. Cardoso1,2 1) INSERM U901, Parc Scientifique de Luminy, Marseille, France; 2) Aix-Marseille University, Marseille, France; 3) Postgenomic Platform, INMED, INSERM, Parc Scientifique de Luminy, Marseille, France; 4) Molecular and Cellular Biology Platform, INMED, INSERM, Parc Scientifique de Luminy, Marseille, France;; 5) Department of Experimental Medicine, University of Genova, Italy; 6) Department of Neuroscience and Brain Technology, Italian Institute of Technology, Genova, Italy;; 7) Laboratory of Neurogenetics, Gaslini Insitute, Genova, Italy.

   The comorbidity of intellectual disabilities (ID) and epilepsy is well recognized but incompletely understood. Many disorders with obvious structural or metabolic effects on the brain directly cause both ID and epilepsy. In certain syndromes, notably the early-onset epileptic encephalopathies, seizures themselves contribute to cognitive deterioration. Genetic knowledge about early epileptic encephalopathies and idiopathic epilepsy has revolutionized the diagnostic approach to these disorders, and an increasing number of gene mutations have been related to their pathogenesis. TBC1D24 is a novel epilepsy-related gene mutated in rare early-onset forms of epilepsy including idiopathic infantile myoclonic epilepsy and severe, drug resistant early onset epilepsy with ID. Additional mutations in TBC1D24 were recently described in siblings affected by malignant migrating partial seizures in infancy. TBC1D24 is mainly expressed in cerebral cortex and hippocampus. TBC1D24 interacts with ARF6, a main regulator of endocyting recycling at plasma membrane and is involved in neurite outgrowth. To get insight into the role of TBC1D24 in cortical development, we used the in utero RNA interference approach, to knockdown TBC1D24 expression in rat embryonic neuronal progenitor cells. Using two different shRNAs, we knocked-down TBC1D24 expression in rat brains at embryonic day 15.5 (E15.5) and showed a delay in radial migration of neurons into the cortical plate at E20, with most of cells showing morpho-functional abnormalities. We also showed that this abnormal migration pattern is not due to defects in the neuronal differentiation. Concomitant expression of wild-type TBC1D24 and shRNA prevented migration delay, whereas pathogenic variants failed to complement RNAi effect, suggesting a loss-of-function mechanism in patients. Analysis at postnatal stage revealed that TBC1D24-knockdown neurons reached appropriate cortical layers, although featuring significant defects in morphological maturation. Next, we showed that concomitant expression of an inactive form of ARF6 was able to rescue the TBC1D24 knockdown phenotype in vivo suggesting that developmental abnormalities of TBC1D24 knockdown model are primary due to an impairment of ARF6 endocyting trafficking. In conclusion, our data revealed a developmentally regulated role of TBC1D24 in cortical formation suggesting that mutations in TBC1D24 may cause subtle alterations in cortical development leading to epilepsy and ID.

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