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The Journal of Neuroscience, January 14, 2009, 29(2):313-327; doi:10.1523/JNEUROSCI.4093-08.2009

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Neurobiology of Disease
Abnormal Network Activity in a Targeted Genetic Model of Human Double Cortex

James B. Ackman, ^* Laurent Aniksztejn, ^* Valérie Crépel, Hélène Becq, Christophe Pellegrino, Carlos Cardoso, Yehezkel Ben-Ari, and Alfonso Represa

Inmed, Inserm, Université de la Méditerranée, 13009 Marseille, France

Correspondence should be addressed to Alfonso Represa, Inmed, Inserm U901, Parc Scientifique et technologique de Luminy, 13009 Marseille, France. Email: represa{at}inmed.univ-mrs.fr

In human patients, cortical dysplasia produced by Doublecortin (DCX) mutations lead to mental retardation and intractable infantile epilepsies, but the underlying mechanisms are not known. DCX^–/– mice have been generated to investigate this issue. However, they display no neocortical abnormality, lessening their impact on the field. In contrast, in utero knockdown of DCX RNA produces a morphologically relevant cortical band heterotopia in rodents. On this preparation we have now compared the neuronal and network properties of ectopic, overlying, and control neurons in an effort to identify how ectopic neurons generate adverse patterns that will impact cortical activity. We combined dynamic calcium imaging and anatomical and electrophysiological techniques and report now that DCX^–/–EGFP⁺-labeled ectopic neurons that fail to migrate develop extensive axonal subcortical projections and retain immature properties, and most of them display a delayed maturation of GABA-mediated signaling. Cortical neurons overlying the heterotopia, in contrast, exhibit a massive increase of ongoing glutamatergic synaptic currents reflecting a strong reactive plasticity. Neurons in both experimental fields are more frequently coactive in coherent synchronized oscillations than control cortical neurons. In addition, both fields displayed network-driven oscillations during evoked epileptiform burst. These results show that migration disorders produce major alterations not only in neurons that fail to migrate but also in their programmed target areas. We suggest that this duality play a major role in cortical dysfunction of DCX brains.

Key words: cortical dysplasia; heterotopia; doublecortin; in utero RNAi; neuronal excitability; rat neocortex

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Received Aug. 27, 2008; revised Nov. 13, 2008; accepted Dec. 2, 2008.

Correspondence should be addressed to Alfonso Represa, Inmed, Inserm U901, Parc Scientifique et technologique de Luminy, 13009 Marseille, France. Email: represa{at}inmed.univ-mrs.fr

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