Epilepsy in Dcx knockout mice associated with discrete lamination defects and enhanced excitability in the hippocampus.
Epilepsy in Dcx knockout mice associated with discrete lamination defects and enhanced excitability in the hippocampus.
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DOI：
10.1371/journal.pone.0002473
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发表时间：
2008-06-25
期刊：
影响因子：
3.7
通讯作者：
Francis F
中科院分区：
文献类型：
--
作者：
Nosten-Bertrand M;Kappeler C;Dinocourt C;Denis C;Germain J;Phan Dinh Tuy F;Verstraeten S;Alvarez C;Métin C;Chelly J;Giros B;Miles R;Depaulis A;Francis F
双皮质素(DCX)突变患者有严重的皮质畸形，与智力低下和癫痫有关。DCX基因敲除(KO)小鼠没有表现出主要的等皮质异常，但有离散的海马区缺陷。我们质疑这些缺陷的功能后果，并在此报告DCX KO小鼠过度活跃并表现出自发性惊厥发作。在大部分KO动物中检测到神经肽Y和钙结合蛋白表达的变化，这种变化与癫痫的发生一致，而惊厥药物，包括海人酸和戊四氮，也更容易在KO小鼠中诱导癫痫发作。我们发现KO海马片中发育不良的CA3区产生尖锐的波样活动，并具有较低的癫痫样事件阈值。视频-脑电监测还表明，自发癫痫发作是在海马区开始的。同样，DCX基因突变的人类患者的癫痫发作可以显示出主要累及颞叶。总之，DCX KO小鼠的癫痫发作很可能是由于涉及海马区异位细胞的异常突触传递所致，因此这些小鼠可能为进一步研究癫痫样活动的起因提供了有用的模型。
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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影响因子：
2.7
作者：
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通讯作者：
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