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

• Published in: Proceedings of the National Academy of Sciences - PNAS 2009-04, Vol.106 (16), p.6766-6771
• Main Authors: Kerjan, Géraldine, Koizumi, Hiroyuki, Han, Edward B, Dubé, Celine M, Djakovic, Stevan N, Patrick, Gentry N, Baram, Tallie Z, Heinemann, Stephen F, Gleeson, Joseph G
• Format: Article
• Language: English
• Subjects: Animals; Biological Sciences; Brain; Cell Differentiation - drug effects; Cell Polarity - drug effects; Complex Systems: From Chemistry to Systems Biology Special Feature; Correlation analysis; Dendrites; Dendrites - drug effects; Dendrites - pathology; Epilepsy; gamma-Aminobutyric Acid - pharmacology; Hippocampus; Hippocampus - embryology; Hippocampus - enzymology; Hippocampus - pathology; Interneurons; Interneurons - drug effects; Interneurons - enzymology; Interneurons - pathology; Kinases; Laminates; Lymphocytes; Mice; Mice, Knockout; Microtubule-Associated Proteins - deficiency; Microtubule-Associated Proteins - metabolism; Mutation; Neurons; Neurons - drug effects; Neurons - enzymology; Neurons - pathology; Neuropeptides - deficiency; Neuropeptides - metabolism; Protein-Serine-Threonine Kinases - deficiency; Protein-Serine-Threonine Kinases - metabolism; Proto-Oncogene Proteins c-fos - metabolism; Pyramidal cells; Pyramidal Cells - drug effects; Pyramidal Cells - enzymology; Pyramidal Cells - pathology; Rodents; Seizures; Seizures - enzymology; Seizures - pathology; Somatostatin - metabolism; Survival Analysis; Synapses - drug effects; Synapses - metabolism; Weaning
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0812687106

Mutations in doublecortin (DCX) 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-null 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.