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Marseille, France

Hadjikhani N.,Biomedical Imaging Center | Hadjikhani N.,Gillberg Neuropsychiatric Center | Zurcher N.R.,Biomedical Imaging Center | Rogier O.,Ecole Polytechnique Federale de Lausanne | And 4 more authors.
Autism | Year: 2015

Clinical observations have shown that GABA-acting benzodiazepines exert paradoxical excitatory effects in autism, suggesting elevated intracellular chloride (Cl-)i and excitatory action of GABA. In a previous double-blind randomized study, we have shown that the diuretic NKCC1 chloride importer antagonist bumetanide, that decreases (Cl-)i and reinforces GABAergic inhibition, reduces the severity of autism symptoms. Here, we report results from an open-label trial pilot study in which we used functional magnetic resonance imaging and neuropsychological testing to determine the effects of 10 months bumetanide treatment in adolescents and young adults with autism. We show that bumetanide treatment improves emotion recognition and enhances the activation of brain regions involved in social and emotional perception during the perception of emotional faces. The improvement of emotion processing by bumetanide reinforces the usefulness of bumetanide as a promising treatment to improve social interactions in autism. © The Author(s) 2013.

Carabalona A.,INMED | Carabalona A.,Aix - Marseille University | Carabalona A.,French Institute of Health and Medical Research | Beguin S.,INMED | And 27 more authors.
Human Molecular Genetics | Year: 2012

Periventricular nodular heterotopia (PH) is a human brain malformation caused by defective neuronal migration that results in ectopic neuronal nodules lining the lateral ventricles beneath a normal appearing cortex. Most affected patients have seizures and their cognitive level varies from normal to severely impaired. Mutations in the Filamin-A (or FLNA) gene are the main cause of PH, but the underlying pathological mechanism remains unknown. Although two FlnA knockout mouse strains have been generated, none of them showed the presence of ectopic nodules. To recapitulate the loss of FlnA function in the developing rat brain, we used an in utero RNA interference-mediated knockdown approach and successfully reproduced a PH phenotype in rats comparable with that observed in human patients. In FlnA-knockdown rats, we report that PH results from a disruption of the polarized radial glial scaffold in the ventricular zone altering progression of neural progenitors through the cell cycle and impairing migration of neurons into the cortical plate. Similar alterations of radial glia are observed in human PH brains of a 35-week fetus and a 3-month-old child, harboring distinct FLNA mutations not previously reported. Finally, juvenile FlnA-knockdown rats are highly susceptible to seizures, confirming the reliability of this novel animal model of PH. Our findings suggest that the disorganization of radial glia is the leading cause of PH pathogenesis associated with FLNA mutations.Rattus norvegicus FlnA mRNA (GenBank accession number FJ416060). © The Author 2011. Published by Oxford University Press. All rights reserved.

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