title: Mice lacking doublecortin and doublecortin-like kinase 2 display altered hippocampal neuronal maturation and spontaneous seizures.
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.
authors.affiliation: Neurogenetics Laboratory, Howard Hughes Medical Institute, Department of Neurosciences, University of California at San Diego, La Jolla, CA 92093, USA.
authors.forename: Géraldine
authors.initials: G
authors.lastname: Kerjan
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Koizumi
authors.forename: Edward B
authors.initials: EB
authors.lastname: Han
authors.forename: Celine M
authors.initials: CM
authors.lastname: Dubé
authors.forename: Stevan N
authors.initials: SN
authors.lastname: Djakovic
authors.forename: Gentry N
authors.initials: GN
authors.lastname: Patrick
authors.forename: Tallie Z
authors.initials: TZ
authors.lastname: Baram
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Heinemann
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Gleeson