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

Nature Medicine volume 15, pages 84–90 (2009)Cite this article

A Corrigendum to this article was published on 07 November 2011

This article has been updated

Abstract

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.

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Figure 1: Temporal control of Dcx expression in mispositioned neurons by using Cre-dependent expression vectors and 4-OHT–activatable Cre recombinase.
Figure 2: Restoration of neocortical lamination and regression of SBH after reexpression of Dcx at P0.
Figure 3: Migration of fated upper layer neurons from SBH.
Figure 4: Morphology of rescued neurons.
Figure 5: Crucial developmental period for regressing malformation.
Figure 6: Decreased seizure susceptibility to pentylenetetrazol-induced seizures.

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Change history

  • 07 November 2011

     In the version of this article initially published, the labels in the key to the bar graph in Figure 2c were incorrect. The gray bars should have been labeled 'Double cortex', and the white bars should have been 'P0 rescue'. The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

CALNL-eGFP and CAG-ERT2CreERT2 were gifts from T. Matsuda and C. Cepko, Harvard Medical School. ImageJ software was from W. Rasband, US National Institutes of Health. NeuronJ 1.2 was from E. Meijering (Erasmus University Medical Center Rotterdam). This work was supported by the US National Institutes of Health (MH056524 and NS062416 to J.J.L.) and the Jerome Lejeune foundation (research fellowship to J.-B.M.).

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Authors and Affiliations

  1. Department of Physiology and Neurobiology, 75 North Eagleville Road U-3156, University of Connecticut, Storrs, 06269, Connecticut, USA

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

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  1. Jean-Bernard Manent
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  2. Yu Wang
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Contributions

J.-B.M. and J.J.L. contributed to all aspects of the project; J.-B.M. conducted histological procedures, seizure induction experiments, quantifications and data analysis; Y.W. performed intrauterine surgeries and interneuron analysis; Y.C. performed confocal microscopy, interneuron analysis and contributed to seizure induction experiments and M.P. constructed the plasmid vectors and contributed to confocal microscopy.

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Correspondence to Joseph J LoTurco.

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Manent, JB., Wang, Y., Chang, Y. et al. Dcx reexpression reduces subcortical band heterotopia and seizure threshold in an animal model of neuronal migration disorder. Nat Med 15, 84–90 (2009). https://doi.org/10.1038/nm.1897

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