Jain Swati, LaFrancois John J, Gerencer Kasey, Botterill Justin J, Kennedy Meghan, Criscuolo Chiara, Scharfman Helen E
Center for Dementia Research, The Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY 10962.
Current address: Department of Psychology, The University of Maine, Orono, ME 04469.
bioRxiv. 2024 Sep 11:2023.07.08.548217. doi: 10.1101/2023.07.08.548217.
Neurogenesis occurs in the adult brain in the hippocampal dentate gyrus, an area that contains neurons which are vulnerable to insults and injury, such as severe seizures. Previous studies showed that increasing adult neurogenesis reduced neuronal damage after these seizures. Because the damage typically is followed by chronic life-long seizures (epilepsy), we asked if increasing adult-born neurons would prevent epilepsy. Adult-born neurons were selectively increased by deleting the pro-apoptotic gene from Nestin-expressing progenitors. Tamoxifen was administered at 6 weeks of age to conditionally delete in Nestin-CreER mice. Six weeks after tamoxifen administration, severe seizures (status epilepticus; SE) were induced by injection of the convulsant pilocarpine. After mice developed epilepsy, seizure frequency was quantified for 3 weeks. Mice with increased adult-born neurons exhibited fewer chronic seizures. Postictal depression was reduced also. These results were primarily in female mice, possibly because they were the more affected by deletion than males, consistent with sex differences in . The female mice with enhanced adult-born neurons also showed less neuronal loss of hilar mossy cells and hilar somatostatin-expressing neurons than wild type females or males, which is notable because these two hilar cell types are implicated in epileptogenesis. The results suggest that selective deletion to increase adult-born neurons can reduce experimental epilepsy, and the effect shows a striking sex difference. The results are surprising in light of past studies showing that suppressing adult-born neurons can also reduce chronic seizures.
神经发生在成体大脑的海马齿状回中，该区域包含易受损伤和伤害的神经元，如严重癫痫发作。先前的研究表明，增加成体神经发生可减少这些癫痫发作后的神经元损伤。由于这种损伤通常会导致慢性终身癫痫发作（癫痫），我们询问增加新生神经元是否能预防癫痫。通过从表达巢蛋白的祖细胞中删除促凋亡基因，选择性地增加了新生神经元。在6周龄时给Nestin-CreER小鼠注射他莫昔芬，以条件性删除该基因。注射他莫昔芬6周后，通过注射惊厥剂毛果芸香碱诱导严重癫痫发作（癫痫持续状态；SE）。在小鼠患癫痫后，对癫痫发作频率进行了3周的量化。新生神经元增加的小鼠慢性癫痫发作较少。发作后抑郁也有所减轻。这些结果主要出现在雌性小鼠中，可能是因为它们比雄性小鼠受该基因缺失的影响更大，这与该基因的性别差异一致。与野生型雌性或雄性小鼠相比，新生神经元增强的雌性小鼠海马苔藓细胞和表达生长抑素的海马神经元的神经元损失也较少，这一点值得注意，因为这两种海马细胞类型与癫痫发生有关。结果表明，通过选择性删除该基因来增加新生神经元可以减少实验性癫痫，且这种效果存在显著的性别差异。鉴于过去的研究表明抑制新生神经元也可以减少慢性癫痫发作，这些结果令人惊讶。
