Aging of Krushinsky-Molodkina audiogenic rats is accompanied with pronounced neurodegeneration and dysfunction of the glutamatergic system in the hippocampus

IF 2.7 4区医学 Q3 NEUROSCIENCES

Brain Research Pub Date : 2024-10-24 DOI:10.1016/j.brainres.2024.149294

Ekaterina P. Aleksandrova , Andrey P. Ivlev , Alexey A. Kulikov , Alexandra A. Naumova , Margarita V. Glazova , Elena V. Chernigovskaya

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Abstract

Advancing age strongly correlates with an increased risk of epilepsy development. On the other hand, epilepsy may exacerbate the negative effects of aging making it pathological. In turn, the possible link between aging and epileptogenesis is dysregulation of glutamatergic transmission. In the present study, we analyzed the functional state of the glutamatergic system in the hippocampus of aging (18-month-old) Krushinsky-Molodkina (KM) audiogenic rats to disclose alterations associated with aging on the background of inherited predisposition to audiogenic seizures (AGS). Naïve KM rats with no AGS experience were recruited in the experiments. Wistar rats of the corresponding age were used as a control. First of all, aging KM rats demonstrated a significant decrease in cell population and synaptopodin expression in the hippocampus indicating enhanced loss of cells and synapses. Meanwhile, elevated phosphorylation of ERK1/2 and CREB and increased glutamate in the neuronal perikarya were revealed indicating increased activity of the rest hippocampal cells and increased glutamate production. However, glutamate in the fibers and synapses was mainly unchanged, and the proteins regulating glutamate exocytosis showed variable changes which could compensate each other and maintain glutamate release at the unchanged level. In addition, we revealed downregulation of NMDA-receptor subunit GluN2B and upregulation of AMPA-receptor GluA2 subunit, which could also prevent overexcitation and support cell survival in the hippocampus of aging KM rats. Nevertheless, abnormally high glutamate production, observed in aging KM rats, may provide the basis for hyperexcitability of the hippocampus and increased seizure susceptibility in old age.

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克鲁辛斯基-莫洛金娜致听大鼠的衰老伴随着明显的神经变性和海马中谷氨酸能系统的功能障碍。

年龄的增长与癫痫发病风险的增加密切相关。另一方面，癫痫可能会加剧衰老的负面影响，使其成为病态。反过来，衰老与癫痫发生之间的可能联系是谷氨酸能传导失调。在本研究中，我们分析了老龄（18 个月大）克鲁欣斯基-莫洛金娜（KM）致听性大鼠海马中谷氨酸能系统的功能状态，以揭示在遗传性致听性癫痫发作（AGS）易感性背景下与老龄相关的改变。实验招募了未经历过 AGS 的纯种 KM 大鼠。相应年龄的 Wistar 大鼠作为对照。首先，衰老的 KM 大鼠表现出海马细胞数量和突触素表达的显著减少，这表明细胞和突触的丢失加剧。同时，ERK1/2 和 CREB 磷酸化升高，神经元周围谷氨酸增加，这表明海马休止期细胞活动增加，谷氨酸分泌增加。然而，神经纤维和突触中的谷氨酸主要没有变化，调节谷氨酸外泌的蛋白质也出现了不同的变化，这些变化可以相互补偿，并将谷氨酸的释放维持在不变的水平。此外，我们还发现了 NMDA 受体亚基 GluN2B 的下调和 AMPA 受体亚基 GluA2 的上调，这也可以防止老化 KM 大鼠海马的过度兴奋并支持细胞存活。然而，在衰老的 KM 大鼠身上观察到的谷氨酸异常高分泌可能是老年海马过度兴奋和癫痫易感性增加的基础。

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来源期刊

Brain Research 医学-神经科学

CiteScore

5.90

自引率

3.40%

发文量

268

审稿时长

47 days

期刊介绍： An international multidisciplinary journal devoted to fundamental research in the brain sciences. Brain Research publishes papers reporting interdisciplinary investigations of nervous system structure and function that are of general interest to the international community of neuroscientists. As is evident from the journals name, its scope is broad, ranging from cellular and molecular studies through systems neuroscience, cognition and disease. Invited reviews are also published; suggestions for and inquiries about potential reviews are welcomed. With the appearance of the final issue of the 2011 subscription, Vol. 67/1-2 (24 June 2011), Brain Research Reviews has ceased publication as a distinct journal separate from Brain Research. Review articles accepted for Brain Research are now published in that journal.