Pten基因敲除癫痫模型中的体生长抑素中间神经元命运图谱和结构。

IF 4.2 3区 医学 Q2 NEUROSCIENCES
Frontiers in Cellular Neuroscience Pub Date : 2024-10-21 eCollection Date: 2024-01-01 DOI:10.3389/fncel.2024.1474613
Austin W Drake, Lilian G Jerow, Justin V Ruksenas, Carlie McCoy, Steve C Danzer
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引用次数: 0

摘要

抑制性中间神经元的中断在癫痫患者的大脑中很常见,据推测,它在癫痫发生过程中起着关键作用。在癫痫状态模型中,中间神经元的突然中断和缺失具有很好的特征,然而,癫痫状态是导致人类癫痫的一个相对罕见的原因。在其他形式的癫痫中,中间神经元的破坏是如何演变的还不太清楚。在这里,我们探讨了体生长抑素(SST)中间神经元干扰如何在四重转基因 Gli1-CreERT2、Ptenfl/fl、SST-FlpO 和 frt-eGFP 小鼠中演变。在这些动物中,当删除齿状颗粒细胞亚群中的哺乳动物雷帕霉素靶蛋白(mTOR)负调控因子磷酸酶和天丝蛋白同源物(Pten)后,癫痫就会发生,而下游表达 Pten 的 SST 神经元会被绿色荧光蛋白(GFP)标记为命运图谱。该模型捕捉到了人类mTOR病的遗传复杂性,其中突变可能仅限于兴奋神经元系,这意味着中间神经元的参与是后期发展和继发性的。在齿状颗粒细胞(DGC)-Pten基因敲除(KOs)中,海马中命运图谱SST神经元的密度降低了,但它们的分子表型没有改变,GFP+细胞对SST和副发光素(PV)免疫反应的百分比相似。齿状回中存活的 SST 神经元具有较大的体节,尽管 SST 细胞丢失,但齿状回分子层中 GFP+ 过程的密度保持不变,这意味着存活的细胞具有代偿性萌发。粒细胞突触前末端的标记物 Znt3 免疫标记点的密度与脊髓中的 GFP+ 过程相对应,其密度有所增加,这表明粒细胞对 SST 神经元的输入增强了。最后,FosB 阳性的 GFP+ 细胞百分比显著增加,这意味着存活的 SST 神经元更加活跃。这些发现共同表明,表达体生长抑素的中间神经元对上游 Pten KO 兴奋性颗粒细胞驱动的过度兴奋和癫痫发作表现出病理(细胞丢失)和适应性(生长)反应的结合。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Somatostatin interneuron fate-mapping and structure in a Pten knockout model of epilepsy.

Disruption of inhibitory interneurons is common in the epileptic brain and is hypothesized to play a pivotal role in epileptogenesis. Abrupt disruption and loss of interneurons is well-characterized in status epilepticus models of epilepsy, however, status epilepticus is a relatively rare cause of epilepsy in humans. How interneuron disruption evolves in other forms of epilepsy is less clear. Here, we explored how somatostatin (SST) interneuron disruption evolves in quadruple transgenic Gli1-CreERT2, Ptenfl/fl, SST-FlpO, and frt-eGFP mice. In these animals, epilepsy develops following deletion of the mammalian target of rapamycin (mTOR) negative regulator phosphatase and tensin homolog (Pten) from a subset of dentate granule cells, while downstream Pten-expressing SST neurons are fate-mapped with green fluorescent protein (GFP). The model captures the genetic complexity of human mTORopathies, in which mutations can be restricted to excitatory neuron lineages, implying that interneuron involvement is later developing and secondary. In dentate granule cell (DGC)-Pten knockouts (KOs), the density of fate-mapped SST neurons was reduced in the hippocampus, but their molecular phenotype was unchanged, with similar percentages of GFP+ cells immunoreactive for SST and parvalbumin (PV). Surviving SST neurons in the dentate gyrus had larger somas, and the density of GFP+ processes in the dentate molecular layer was unchanged despite SST cell loss and expansion of the molecular layer, implying compensatory sprouting of surviving cells. The density of Znt3-immunolabeled puncta, a marker of granule cell presynaptic terminals, apposed to GFP+ processes in the hilus was increased, suggesting enhanced granule cell input to SST neurons. Finally, the percentage of GFP+ cells that were FosB positive was significantly increased, implying that surviving SST neurons are more active. Together, findings suggest that somatostatin-expressing interneurons exhibit a combination of pathological (cell loss) and adaptive (growth) responses to hyperexcitability and seizures driven by upstream Pten KO excitatory granule cells.

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来源期刊
CiteScore
7.90
自引率
3.80%
发文量
627
审稿时长
6-12 weeks
期刊介绍: Frontiers in Cellular Neuroscience is a leading journal in its field, publishing rigorously peer-reviewed research that advances our understanding of the cellular mechanisms underlying cell function in the nervous system across all species. Specialty Chief Editors Egidio D‘Angelo at the University of Pavia and Christian Hansel at the University of Chicago are supported by an outstanding Editorial Board of international researchers. This multidisciplinary open-access journal is at the forefront of disseminating and communicating scientific knowledge and impactful discoveries to researchers, academics, clinicians and the public worldwide.
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