Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Differentiation* / drug effects
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Cell Polarity / drug effects
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Dendrites / drug effects
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Dendrites / pathology
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Doublecortin Domain Proteins
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Doublecortin Protein
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Hippocampus / embryology
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Hippocampus / enzymology*
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Hippocampus / pathology*
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Interneurons / drug effects
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Interneurons / enzymology
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Interneurons / pathology
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Mice
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Mice, Knockout
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Microtubule-Associated Proteins / deficiency*
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Microtubule-Associated Proteins / metabolism
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Neurons / drug effects
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Neurons / enzymology*
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Neurons / pathology
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Neuropeptides / deficiency*
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Neuropeptides / metabolism
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Protein Serine-Threonine Kinases / deficiency*
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Protein Serine-Threonine Kinases / metabolism
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Proto-Oncogene Proteins c-fos / metabolism
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Pyramidal Cells / drug effects
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Pyramidal Cells / enzymology
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Pyramidal Cells / pathology
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Seizures / enzymology*
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Seizures / pathology
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Somatostatin / metabolism
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Survival Analysis
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Synapses / drug effects
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Synapses / metabolism
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Weaning
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gamma-Aminobutyric Acid / pharmacology
Substances
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DCX protein, human
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Dcx protein, mouse
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Doublecortin Domain Proteins
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Doublecortin Protein
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Microtubule-Associated Proteins
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Neuropeptides
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Proto-Oncogene Proteins c-fos
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Somatostatin
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gamma-Aminobutyric Acid
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Dclk2 protein, mouse
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Protein Serine-Threonine Kinases