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 dosagedependent disrupted hippocampal lamination associated with a cellautonomous 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.epilepsy ͉ receptive field ͉ pyramidal neuron ͉ dendrites ͉ delamination A pproximately 1 in 10 people will have a seizure sometime during their life, and the prevalence of epilepsy in the general population is Ϸ3%. Cortical dysplasia, which includes defects in both neocortex and hippocampus, can result from disordered neuronal cell proliferation, migration, or differentiation, and is identified in Ͼ25% of children with intractable epilepsy (1), the type of epilepsy associated with the highest morbidity and mortality.Classical lissencephaly (defined as smooth brain, with simplified or absent gyri and sulci) is due to alterations in neuronal migration and differentiation. The frequency of epilepsy in lissencephaly is probably 100%, and is typically associated with lethality in the first or second decade of life. One of the major causative genes in humans is doublecortin (DCX), which encodes a microtubule binding and stabilizing protein (2).DCX has 2 close homologues in mice, doublecortin-like kinase 1 (Dclk1, also known as Dcamkl1) and doublecortin-like kinase 2 (Dclk2, also known as Dck2), both with broad nervous system expression, to include both mitotic neuroblasts and adult neurons, whereas Dcx is mostly expressed in postmitotic immature neurons, and also transiently in adult neuroblasts (3). Previous analysis of Dcx; Dclk1 double knockouts demonstrated functional redundancy during cortical and hippocampal lamination (4, 5). To further uncover functional redundancy in the DCX gene family, we targeted Dclk2, a gene encoding a highly conserved N-terminal doublecortin domain and a C-terminal kinase domain-containing protein (6). Here, we report that mice deficient in both Dcx and Dclk2 display frequent and spontaneous epileptic seizures, bearing some resemblance to the phenotype observed in humans. Results Dclk2 Knockout Leav...

LIS1 Deficiency Promotes Dysfunctional Synaptic Integration of Granule Cells Generated in the Developing and Adult Dentate Gyrus

“…The convergence of these features in a mouse model could have significant consequences for circuit information processing and/or contribute to the generation of pathological network excitability associated with type I lissencephaly. A number of genetically based animal models of MCD have been developed, and most show robust hyperexcitability and/or spontaneous seizures (Wenzel et al, 2001;Kellinghaus et al 2004;Patel et al, 2004;Kwon et al, 2006;Harrington et al, 2007;Patrylo and Willingham, 2007;Nosten-Bertrand et al, 2008;Greenwood et al, 2009;Kerjan et al, 2009). When synaptic mechanisms have been investigated, these studies have typically reported postsynaptic alterations in glutamatergic excitatory Auerbach et al, 2011;Bateup et al, 2011;Luikart et al, 2011) or GABAergic inhibitory currents (Trotter et al, 2006;Ackman et al, 2009).…”

Genetics and mechanisms leading to human cortical malformations

“…The cingulate cortex was also affected in contrast to Dcx and Dclk single KO mice, which show no apparent neocortical defects [108]. Double mutants of Dcx and Dclk2 have also been generated, however in this case the hippocampus is the most affected structure [112].…”

Topographical transcriptome mapping of the mouse medial ganglionic eminence by spatially-resolved RNA-seq

“…Sox 2 [27][28][29] and COUP transcription factor 1 (Couptf1), also known as Nr2f2, [26,30] were chosen as markers for cluster 1, and in situ hybridization for both genes showed their expression restricted to the ventricular zone, as expected ( Figure 4A-H). For cluster 2, in situ hybridization for Doublecortin like kinase 2 (Dclk2) and Sox11 [31,32] delineated a narrow region immediately ventral to the ventricular zone, matching the expected location of this cluster ( Figure 4I-L). In situ hybridization for cluster 3 gene Melanoma antigen family D1 (Maged1) labeled an area immediately dorsal to the Gap43 signal, also matching the expected spatial location of this cluster ( Figure 4Q-T).…”