Dcx reexpression reduces subcortical band heterotopia and seizure threshold in an animal model of neuronal migration disorder.
Disorders of neuronal migration can lead to malformations of the cerebral neocortex that greatly increase the risk of seizures. It remains untested whether malformations caused by disorders in neuronal migration can be reduced by reactivating cellular migration and whether such repair can decrease seizure risk. Here we show, in a rat model of subcortical band heterotopia (SBH) generated by in utero RNA interference of the Dcx gene, that aberrantly positioned neurons can be stimulated to migrate by reexpressing Dcx after birth. Restarting migration in this way both reduces neocortical malformations and restores neuronal patterning. We further find that the capacity to reduce SBH continues into early postnatal development. Moreover, intervention after birth reduces the convulsant-induced seizure threshold to a level similar to that in malformation-free controls. These results suggest that disorders of neuronal migration may be eventually treatable by reengaging developmental programs both to reduce the size of cortical malformations and to reduce seizure risk.
Manent
Jean-Bernard
JB
Department of Physiology and Neurobiology, University of Connecticut, Storrs, CT 06269, USA.
Wang
Yu
Y
Chang
Yoonjeung
Y
Paramasivam
Murugan
M
LoTurco
Joseph J
JJ
D000818:Animals; D030801:Animals, Genetically Modified; D002465:Cell Movement / Q000235:genetics; D054221:Classical Lissencephalies and Subcortical Band Heterotopias / Q000235:genetics* / Q000473:pathology / Q000628:therapy / Q000662:veterinary; D004195:Disease Models, Animal; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D005260:Female; D055785:Gene Knockdown Techniques; D020022:Genetic Predisposition to Disease; D015316:Genetic Therapy; D054081:Malformations of Cortical Development, Group II / Q000196:embryology / Q000235:genetics / Q000473:pathology / Q000662:veterinary; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000502:physiology; D008954:Models, Biological; D009474:Neurons / Q000473:pathology / Q000502:physiology; D009479:Neuropeptides / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000502:physiology; D011247:Pregnancy; D034622:RNA Interference / Q000502:physiology; D051381:Rats; D012640:Seizures / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D012720:Severity of Illness Index
C000714848:Dcx protein, rat; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D008869:Microtubule-Associated Proteins; D009479:Neuropeptides