title: Abnormal network activity in a targeted genetic model of human double cortex.
abstract: 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.
authors.affiliation: Inmed, Inserm, Université de la Méditerranée, Marseille, France.
authors.forename: James B
authors.initials: JB
authors.lastname: Ackman
authors.forename: Laurent
authors.initials: L
authors.lastname: Aniksztejn
authors.forename: Valérie
authors.initials: V
authors.lastname: Crépel
authors.forename: Hélène
authors.initials: H
authors.lastname: Becq
authors.forename: Christophe
authors.initials: C
authors.lastname: Pellegrino
authors.forename: Carlos
authors.initials: C
authors.lastname: Cardoso
authors.forename: Yehezkel
authors.initials: Y
authors.lastname: Ben-Ari
authors.forename: Alfonso
authors.initials: A
authors.lastname: Represa
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D030801:Animals, Genetically Modified; D000831:Animals, Newborn; D001640:Bicuculline / Q000494:pharmacology; D002540:Cerebral Cortex / Q000002:abnormalities* / Q000187:drug effects / Q000196:embryology / Q000473:pathology; D004195:Disease Models, Animal; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D018274:Electroporation / Q000379:methods; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005260:Female; D018756:GABA Antagonists / Q000494:pharmacology; D005968:Glutamate Decarboxylase / Q000378:metabolism; D018698:Glutamic Acid / Q000494:pharmacology; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D066298:In Vitro Techniques; D054220:Malformations of Cortical Development / Q000235:genetics* / Q000473:pathology*; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D008869:Microtubule-Associated Proteins / Q000235:genetics; D009154:Mutation / Q000235:genetics; D009415:Nerve Net / Q000187:drug effects / Q000503:physiopathology*; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D009479:Neuropeptides / Q000235:genetics; D011247:Pregnancy; D011810:Quinoxalines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
chemical_list: C000714328:DCX protein, human; C000714847:Dcx protein, mouse; C000714848:Dcx protein, rat; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D018691:Excitatory Amino Acid Antagonists; D018756:GABA Antagonists; D008869:Microtubule-Associated Proteins; D009479:Neuropeptides; D011810:Quinoxalines; D034741:RNA, Small Interfering; D026941:Sodium Channel Blockers; C485184:enhanced green fluorescent protein; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; D049452:Green Fluorescent Proteins; D018698:Glutamic Acid; D013779:Tetrodotoxin; D005680:gamma-Aminobutyric Acid; C056639:2-amino-5-phosphopentanoic acid; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1; D014633:Valine; D001640:Bicuculline