Article

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

INSERM, U513, Université Pierre et Marie Curie, Paris, France.
PLoS ONE (Impact Factor: 3.23). 02/2008; 3(6):e2473. DOI: 10.1371/journal.pone.0002473
Source: PubMed

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.

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    • "The same DC domain is found in other members of the Dcx family, such as Dcx-like kinases (Dclk1 and 2), and is followed in these proteins by a kinase domain [16] [17]. Compared to humans, mice deficient for Dcx show a milder phenotype with an abnormal hippocampal pyramidal cell layer but normal neocortical lamination [18] [19] [20]. However, the Dclk1 and Dcx double knockout phenotype shows more severe cortical disorganization, resembling the human phenotype for DCX mutations, suggesting a functional redundancy between the two genes [21] [22]. "
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    ABSTRACT: Mutations in the microtubule-associated protein doublecortin (DCX) cause type I (X-linked or XLIS) lissencephaly in hemizygous males and subcortical band heterotopia (SBH) in females, with defects in neuron migration during development affecting cortical lamination. We found that besides its well-established expression in migrating neurons of the brain, doublecortin (Dcx in mice) is also expressed in motor neurons and skeletal muscle in embryonic neuromuscular junctions (NMJs), raising the possibility of a role in synaptogenesis. Studies with whole-mount preparations of embryonic mouse diaphragm revealed that loss of Dcx leads to abnormal presynaptic arborization and a significantly increased incidence of short axonal extensions beyond innervated acetylcholine receptor (AChR) clusters in the developing NMJ. This phenotype, albeit relatively mild, suggests that Dcx contributes to a stop/stabilizing signal at the synapse, which normally limits further axonal growth following establishment of synaptic contact with the postsynaptic element. Importantly, we also identified abnormal and denervated NMJs in a muscle biopsy from a 16-year-old female patient with SBH, showing both profound presynaptic and postsynaptic morphological defects. Overall, these combined results point to a critical role of doublecortin in the formation of the NMJ. Copyright © 2015 Elsevier B.V. All rights reserved.
    Neuromuscular Disorders 02/2015; 25(6). DOI:10.1016/j.nmd.2015.01.012 · 3.13 Impact Factor
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    • "Both models suggested that hyperthermic seizures might leave their imprint on the developing brain by altering the way neurons differentiate, connect and communicate with each other, even if such changes may be ultimately compensated for in the absence of a second event. Here, we explored the consequences of a single episode of prolonged hyperthermic seizures in P10 mice pups as a " singlehit " , and secondarily investigated whether such a single episode could aggravate a preceding or subsequent epileptogenic insult, using two models of hippocampal epilepsy: (i) the Dcx knockout C57BL/6J mouse that displays a hippocampal dysplasia in the CA3 leading to spontaneous seizures in 30% of the cases (Nosten-Bertrand et al., 2008) and (ii) the MTLE mouse model obtained by intra-hippocampal injection of kainate in C57BL/6J adult mice (Heinrich et al., 2006; Maroso et al., 2010; Riban et al., 2002). In human MTLE, secondary generalized tonic–clonic seizures are rare (Maillard et al., 2004), in contrast, focal mesio-temporal lobe (e.g., hippocampal) seizures remain quite frequent, generally resistant to most anti-epileptic drugs and invalidating for the patients (French et al., 1993; Williamson et al., 1993). "
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    • "We chose to induce generalized-like seizures using pentylenetetrazol in a group of implanted animals (n = 7 MAM E14, n = 6 control) and temporolimbic-like seizures using pilocarpine injections (n = 7 MAM E14, n = 5 control) under EEG control. We found no difference in the latency to status induced with lithiumpilocarpine , neither in the time to the first electrographic seizures with pentylenetetrazol (Table 2), in contrast to previous data from transplacental MAM models and Dcx-KO mice (Chevassus- Au-Louis et al., 1998a; Nosten-Bertrand et al., 2008). Of note, the time to the first pilocarpine-induced seizure was longer in MAMinjected mice and they exhibited fewer seizures before the status onset as compared with control (Table 2), suggesting that once an hyperexcitable state is reached they quickly progress into status. "
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    ABSTRACT: Developmental cortical malformations comprise a large spectrum of histopathological brain abnormalities and syndromes. Their genetic, developmental and clinical complexity suggests they should be better understood in terms of the complementary action of independently timed perturbations (i.e., the multiple-hit hypothesis). However, understanding the underlying biological processes remains puzzling. Here we induced developmental cortical malformations in offspring, after intraventricular injection of methylazoxymethanol (MAM) in utero in mice. We combined extensive histological and electrophysiological studies to characterize the model. We found that MAM injections at E14 and E15 induced a range of cortical and hippocampal malformations resembling histological alterations of specific genetic mutations and transplacental mitotoxic agent injections. However, in contrast to most of these models, intraventricularly MAM-injected mice remained asymptomatic and showed no clear epilepsy-related phenotype as tested in long-term chronic recordings and with pharmacological manipulations. Instead, they exhibited a non-specific reduction of hippocampal-related brain oscillations (mostly in CA1); including theta, gamma and HFOs; and enhanced thalamocortical spindle activity during non-REM sleep. These data suggest that developmental cortical malformations do not necessarily correlate with epileptiform activity. We propose that the intraventricular in utero MAM approach exhibiting a range of rhythmopathies is a suitable model for multiple-hit studies of associated neurological disorders.
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