Center for Dementia Research, The Nathan S. Kline Institute for Psychiatric Research, Orangeburg, United States.
Department of Anatomy, Physiology, & Pharmacology, College of Medicine, University of Saskatchewan, Saskatoon, Canada.
Elife. 2024 Oct 24;12:RP90893. doi: 10.7554/eLife.90893.
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 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 loss of these two hilar cell types is 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.
成年大脑中的神经发生发生在海马齿状回，这是一个易受刺激和损伤（如严重癫痫发作）的神经元区域。先前的研究表明，增加成年神经发生可以减少这些癫痫发作后的神经元损伤。因为损伤通常会导致慢性终身性癫痫（癫痫），我们想知道增加成年神经元是否可以预防癫痫。通过删除神经前体细胞中表达的促凋亡基因 来选择性地增加成年神经元。在 6 周龄时用他莫昔芬处理以条件性删除 Nestin-CreER 小鼠中的 。在给予他莫昔芬 6 周后，通过注射致惊厥剂匹罗卡品诱导严重癫痫发作（癫痫持续状态；SE）。在小鼠发生癫痫后，对癫痫发作频率进行了 3 周的定量检测。具有增加的成年神经元的小鼠表现出较少的慢性癫痫发作。发作后抑郁也减少了。这些结果主要在雌性小鼠中观察到，这可能是因为与雄性相比，雌性对 缺失的影响更大，这与 在性别上的差异一致。具有增强的成年神经元的雌性小鼠的海马齿状回中的颗粒细胞和海马 somatostatin 表达神经元的神经元丢失也比野生型雌性或雄性少，这值得注意，因为这两种海马细胞类型的丢失与癫痫发生有关。结果表明，选择性地删除 以增加成年神经元可以减少实验性癫痫，并且这种作用表现出明显的性别差异。鉴于过去的研究表明抑制成年神经元也可以减少慢性癫痫发作，这一结果令人惊讶。
