A glial origin for periventricular nodular heterotopia caused by impaired expression of Filamin-A

Periventricularnodularheterotopia(PH)isahumanbrainmalformationcausedbydefectiveneuronalmigrationthat results in ectopic neuronal nodules lining the lateral ventricles beneath a normal appearing cortex. Mostaffected patients have seizures and their cognitive level varies from normal to severely impaired. MutationsintheFilamin-A (or FLNA)genearethemain cause ofPH,but theunderlyingpathologicalmechanism remainsunknown.AlthoughtwoFlnAknockoutmousestrainshavebeengenerated,noneofthemshowedthepresenceofectopicnodules.TorecapitulatethelossofFlnAfunctioninthedevelopingratbrain,weusedaninuteroRNAinterference-mediated knockdown approach and successfully reproduced a PH phenotype in rats comparablewiththatobservedinhumanpatients.InFlnA-knockdownrats,wereportthatPHresultsfromadisruptionofthepolarizedradialglialscaffoldintheventricularzonealteringprogressionofneuralprogenitorsthroughthecellcycleandimpairingmigrationofneuronsintothecorticalplate.SimilaralterationsofradialgliaareobservedinhumanPHbrainsofa35-weekfetusanda3-month-oldchild,harboringdistinctFLNAmutationsnotpreviouslyreported. Finally, juvenile FlnA-knockdown rats are highly susceptible to seizures, confirming the reliability ofthisnovelanimalmodelofPH.OurfindingssuggestthatthedisorganizationofradialgliaistheleadingcauseofPH pathogenesis associated with FLNA mutations.Rattus norvegicus FlnA mRNA (GenBank accession number FJ416060).