Journal Article

Dcx reexpression reduces subcortical band heterotopia and seizure threshold in an animal model of neuronal migration disorder

Chang, YoonJeung, LoTurco, Joseph J, Manent, Jean-Bernard, Paramasivam, Murugan, Wang, Yu

2009

Overview

Aberrant neuronal migration during development leads to defects in cortical development and to an increased seizure susceptibility. Now, Joseph LoTurco and his colleagues show that it is possible to re-invoke neuronal migration perinatally in rodents and reposition neurons into their correct cortical location ( pages 17–18 ). 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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: Animal models / Animals / Animals, Genetically Modified / Biomedical and Life Sciences / Biomedicine / Brain / Cancer Research / Cell adhesion & migration / Cell Movement - genetics / Classical Lissencephalies and Subcortical Band Heterotopias - genetics / Classical Lissencephalies and Subcortical Band Heterotopias - pathology / Classical Lissencephalies and Subcortical Band Heterotopias - therapy / Classical Lissencephalies and Subcortical Band Heterotopias - veterinary / Convulsions & seizures / Disease Models, Animal / Doublecortin Domain Proteins / Doublecortin Protein / Epilepsy / Female / Gene expression / Gene Knockdown Techniques / Gene mutations / Genetic aspects / Genetic Predisposition to Disease / Genetic Therapy / Health aspects / Infectious Diseases / Malformations of Cortical Development, Group II - embryology / Malformations of Cortical Development, Group II - genetics / Malformations of Cortical Development, Group II - pathology / Malformations of Cortical Development, Group II - veterinary / Metabolic Diseases / Microtubule-Associated Proteins - antagonists & inhibitors / Microtubule-Associated Proteins - genetics / Microtubule-Associated Proteins - physiology / Models, Biological / Molecular Medicine / Neurons / Neurons - pathology / Neurons - physiology / Neuropeptides - antagonists & inhibitors / Neuropeptides - genetics / Neuropeptides - physiology / Neurosciences / Physiological aspects / Pregnancy / Rats / Risk factors / RNA Interference - physiology / Rodents / Seizures - genetics / Seizures - pathology / Seizures - therapy / Severity of Illness Index