Epilepsy in Dcx Knockout Mice Associated with Discrete Lamination Defects and Enhanced Excitability in the Hippocampus

Abstract

Patients with Doublecortin (DCX) mutations have severe cortical malformations associated with mental retardation and epilepsy. Dcx knockout (KO) mice show no major isocortical abnormalities, but have discrete hippocampal defects. We questioned the functional consequences of these defects and report here that Dcx KO mice are hyperactive and exhibit spontaneous convulsive seizures. Changes in neuropeptide Y and calbindin expression, consistent with seizure occurrence, were detected in a large proportion of KO animals, and convulsants, including kainate and pentylenetetrazole, also induced seizures more readily in KO mice. We show that the dysplastic CA3 region in KO hippocampal slices generates sharp wave-like activities and possesses a lower threshold for epileptiform events. Video-EEG monitoring also demonstrated that spontaneous seizures were initiated in the hippocampus. Similarly, seizures in human patients mutated for DCX can show a primary involvement of the temporal lobe. In conclusion, seizures in Dcx KO mice are likely to be due to abnormal synaptic transmission involving heterotopic cells in the hippocampus and these mice may therefore provide a useful model to further study how lamination defects underlie the genesis of epileptiform activities.

Genetics and mechanisms leading to human cortical malformations

“…Pyramidal cells displayed morphological abnormalities, as they were smaller with a reduced total dendritic length, and were more excitable than WT cells. In vitro hyperexcitability and spontaneous epilepsy are characteristic of this mouse model [107].…”

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).…”

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

“…Nosten-Bertrand et al (24) recently published that Dcx single nulls can develop rare seizures. A potential explanation for this discrepancy is the use of the C57BL/6N (B6) background by Nosten-Bertrand et al (24), which is associated with a lowered seizure threshold in some mutant mice (25), whereas we used a mixed 129/SvJ and B6 background.…”