Mice lacking doublecortin and doublecortin-like kinase 2 display altered hippocampal neuronal maturation and spontaneous seizures

Géraldine Kerjan, Hiroyuki Koizumi, Edward B. Han, Celine M. Dubé, Stevan N. Djakovic, Gentry N. Patrick, Tallie Z. Baram, Stephen F. Heinemann, Joseph G. Gleeson

Research output: Contribution to journalArticlepeer-review

62 Scopus citations

Abstract

Mutations in doublecortin (OCX) are associated with intractable epilepsy in humans, due to a severe disorganization of the neocortex and hippocampus known as classical lissencephaly. However, the basis of the epilepsy in lissencephaly remains unclear. To address potential functional redundancy with murin Dcx, we targeted one of the closest homologues, doublecortin-like kinase 2 (Dclk2). Here, we report that Dcx; Dclk2-nu\\ mice display frequent spontaneous seizures that originate in the hippocampus, with most animals dying in the first few months of life. Elevated hippocampal expression of c-fos and loss of somatostatin-positive interneurons were identified, both known to correlate with epilepsy. Dcx and Dclk2 are coexpressed in developing hippocampus, and, in their absence, there is dosage-dependent disrupted hippocampal lamination associated with a cell-autonomous simplification of pyramidal dendritic arborizations leading to reduced inhibitory synaptic tone. These data suggest that hippocampal dysmaturation and insufficient receptive field for inhibitory input may underlie the epilepsy in lissencephaly, and suggest potential therapeutic strategies for controlling epilepsy in these patients.

Original languageEnglish
Pages (from-to)6766-6771
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number16
DOIs
StatePublished - Apr 21 2009

Keywords

  • Delamination
  • Dendrites
  • Epilepsy
  • Pyramidal neuron
  • Receptive field

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