新生成的细胞的神经元分化减少是慢性颞叶癫痫中海马神经发生减少的基础。

Decreased neuronal differentiation of newly generated cells underlies reduced hippocampal neurogenesis in chronic temporal lobe epilepsy.

机构信息

Department of Surgery (Neurosurgery), Duke University Medical Center, Durham, North Carolina 27710, USA.

出版信息

Hippocampus. 2010 Jan;20(1):97-112. doi: 10.1002/hipo.20594.

Abstract

Hippocampal neurogenesis declines substantially in chronic temporal lobe epilepsy (TLE). However, it is unclear whether this decline is linked to altered production of new cells and/or diminished survival and neuronal fate-choice decision of newly born cells. We quantified different components of hippocampal neurogenesis in rats exhibiting chronic TLE. Through intraperitoneal administration of 5'-bromodeoxyuridine (BrdU) for 12 days, we measured numbers of newly born cells in the subgranular zone-granule cell layer (SGZ-GCL) at 24 h and 2.5 months post-BrdU administration. Furthermore, the differentiation of newly added cells into neurons and glia was quantified via dual immunofluorescence for BrdU and various markers of neurons and glia. Addition of new cells to the SGZ-GCL over 12 days was comparable between the chronically epileptic hippocampus and the age-matched intact hippocampus. Furthermore, comparison of BrdU+ cells measured at 24 h and 2.5 months post-BrdU administration revealed similar survival of newly born cells between the two groups. However, only 4-5% of newly born cells (i.e., BrdU+ cells) differentiated into neurons in the chronically epileptic hippocampus, in comparison to 73-80% of such cells exhibiting neuronal differentiation in the intact hippocampus. Moreover, differentiation of newly born cells into S-100beta+ astrocytes or NG2+ oligodendrocyte progenitors increased to approximately 79% in the chronically epileptic hippocampus from approximately 25% observed in the intact hippocampus. Interestingly, the extent of proliferation of astrocytes and microglia (identified through Ki-67 and S-100beta and Ki-67 and OX-42 dual immunofluorescence) in the SGZ-GCL was similar between the chronically epileptic hippocampus and the age-matched intact hippocampus, implying that the proliferation of neural stem/progenitor cells in the SGZ-GCL of the chronically epileptic hippocampus was not obscured by an increased division of glia. Thus, severely diminished DG neurogenesis in chronic TLE is not associated with either decreased production of new cells or reduced survival of newly born cells in the SGZ-GCL. Rather, it is linked to a dramatic decline in the neuronal fate-choice decision of newly generated cells. Overall, the differentiation of newly born cells turns mainly into glia with chronic TLE from predominantly neuronal differentiation seen in control conditions.

摘要

海马神经发生在慢性颞叶癫痫(TLE)中显著减少。然而,目前尚不清楚这种减少是否与新细胞产生的改变以及新生成细胞的存活和神经元命运选择决定有关。我们在患有慢性 TLE 的大鼠中定量了海马神经发生的不同成分。通过腹腔内给予 5'-溴脱氧尿苷(BrdU)12 天,我们在 BrdU 给药后 24 小时和 2.5 个月测量了颗粒下区-颗粒细胞层(SGZ-GCL)中新生成细胞的数量。此外,通过 BrdU 和各种神经元和神经胶质标志物的双重免疫荧光定量了新添加细胞向神经元和神经胶质的分化。在 12 天内,新细胞添加到 SGZ-GCL 的速度在慢性癫痫海马体和年龄匹配的完整海马体之间是可比的。此外,比较 BrdU 给药后 24 小时和 2.5 个月测量的 BrdU+细胞,发现两组之间新生成细胞的存活相似。然而,只有 4-5%的新生成细胞(即 BrdU+细胞)在慢性癫痫海马体中分化为神经元,而在完整海马体中,有 73-80%的新生成细胞表现出神经元分化。此外,新生成细胞向 S-100beta+星形胶质细胞或 NG2+少突胶质细胞祖细胞的分化在慢性癫痫海马体中增加到约 79%,而在完整海马体中观察到的约 25%。有趣的是,SGZ-GCL 中星形胶质细胞和小胶质细胞(通过 Ki-67 和 S-100beta 和 Ki-67 和 OX-42 双重免疫荧光鉴定)的增殖程度在慢性癫痫海马体和年龄匹配的完整海马体之间相似,这表明慢性癫痫海马体 SGZ-GCL 中的神经干细胞/祖细胞增殖并没有被胶质细胞的分裂增加所掩盖。因此,慢性 TLE 中 DG 神经发生严重减少与新细胞产生减少或 SGZ-GCL 中新生成细胞存活减少无关。相反,它与新生成细胞的神经元命运选择决定显著下降有关。总体而言,与对照条件下主要的神经元分化相比,慢性 TLE 中新生成细胞的分化主要转向胶质细胞。

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