Conditional Disabled-1 Deletion in Mice Alters Hippocampal Neurogenesis and Reduces Seizure Threshold.
Conditional Disabled-1 Deletion in Mice Alters Hippocampal Neurogenesis and Reduces Seizure Threshold.
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DOI：
10.3389/fnins.2016.00063
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发表时间：
2016
影响因子：
4.3
通讯作者：
Parent JM
中科院分区：
文献类型：
--
作者：
Korn MJ;Mandle QJ;Parent JM
许多颞叶癫痫（TLE）的动物模型表现出齿状回颗粒下区（SGZ）内的祖细胞发生改变。新的神经元异常整合到现有的电路被认为有助于癫痫发生。特别是，成人出生的神经元表现出异位迁移和肺门基底树突（HBDs）被认为是促癫痫。reelin信号的丢失可能导致癫痫患者的这些形态学变化。我们以前证明，有条件删除的reelin衔接蛋白，残疾人-1（Dab 1），从出生后的小鼠SGZ祖细胞产生的齿状颗粒细胞（DGCs）异常树突发育和异位安置。为了确定出生后早期reelin信号的丢失是否是致癫痫的，我们在出生后7-8天有条件地删除了神经祖细胞及其后代中的Dab 1，并在8-10周后进行慢性视频EEG记录。Dab 1缺陷小鼠没有自发性癫痫发作，但表现出发作间期癫痫样异常和毛果芸香碱诱导的癫痫持续状态的潜伏期显着减少。在化学惊厥治疗后，超过90%的Dab 1缺陷小鼠发生全身性运动性惊厥，伴有强直阵挛运动、直立和跌倒，而野生型小鼠<20%。通过Cre报告基因表达测量的缓解效率与第一次持续性癫痫发作的时间呈负相关。这些促癫痫变化与神经发生减少和门部异位DGC数量增加有关。有趣的是，共表达Cre报告基因的神经元包括这些门部异位DGC细胞的一部分，这表明了对于reelin信号传导的损失的非细胞自主效应。我们还注意到CA 1锥体层的分散，可能是由于条件Dab 1等位基因的亚形态效应，但这种异常与癫痫发作易感性无关。这些研究结果表明，出生后产生的DGC的错位或减少有助于异常电路的发展和过度兴奋，但异常的神经发生后，条件Dab 1删除单独是不足以产生自发性癫痫发作。
Many animal models of temporal lobe epilepsy (TLE) exhibit altered neurogenesis arising from progenitors within the dentate gyrus subgranular zone (SGZ). Aberrant integration of new neurons into the existing circuit is thought to contribute to epileptogenesis. In particular, adult-born neurons that exhibit ectopic migration and hilar basal dendrites (HBDs) are suggested to be pro-epileptogenic. Loss of reelin signaling may contribute to these morphological changes in patients with epilepsy. We previously demonstrated that conditional deletion of the reelin adaptor protein, disabled-1 (Dab1), from postnatal mouse SGZ progenitors generated dentate granule cells (DGCs) with abnormal dendritic development and ectopic placement. To determine whether the early postnatal loss of reelin signaling is epileptogenic, we conditionally deleted Dab1 in neural progenitors and their progeny on postnatal days 7–8 and performed chronic video-EEG recordings 8–10 weeks later. Dab1-deficient mice did not have spontaneous seizures but exhibited interictal epileptiform abnormalities and a significantly reduced latency to pilocarpine-induced status epilepticus. After chemoconvulsant treatment, over 90% of mice deficient for Dab1 developed generalized motor convulsions with tonic-clonic movements, rearing, and falling compared to <20% of wild-type mice. Recombination efficiency, measured by Cre reporter expression, inversely correlated with time to the first sustained seizure. These pro-epileptogenic changes were associated with decreased neurogenesis and increased numbers of hilar ectopic DGCs. Interestingly, neurons co-expressing the Cre reporter comprised a fraction of these hilar ectopic DGCs cells, suggesting a non-cell autonomous effect for the loss of reelin signaling. We also noted a dispersion of the CA1 pyramidal layer, likely due to hypomorphic effects of the conditional Dab1 allele, but this abnormality did not correlate with seizure susceptibility. These findings suggest that the misplacement or reduction of postnatally-generated DGCs contributes to aberrant circuit development and hyperexcitability, but aberrant neurogenesis after conditional Dab1 deletion alone is not sufficient to produce spontaneous seizures.