Jiangsu Province Key Laboratory of Anesthesiology, NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, Xuzhou, China.
Department of Anesthesiology and Perioperative Medicine, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai, China.
CNS Neurosci Ther. 2024 Sep;30(9):e70024. doi: 10.1111/cns.70024.
Type 2 diabetes mellitus (T2DM) is related to an increased risk of postoperative cognitive dysfunction (POCD), which may be caused by neuronal hyperexcitability. Astrocyte glutamate transporter 1 (GLT-1) plays a crucial role in regulating neuron excitability. We investigated if T2DM would magnify the increased neuronal excitability induced by anesthesia/surgery (A/S) and lead to POCD in young adult mice, and if so, determined whether these effects were associated with GLT-1 expression.
T2DM model was induced by high fat diet (HFD) and injecting STZ. Then, we evaluated the spatial learning and memory of T2DM mice after A/S with the novel object recognition test (NORT) and object location test (OLT). Western blotting and immunofluorescence were used to analyze the expression levels of GLT-1 and neuronal excitability. Oxidative stress reaction and neuronal apoptosis were detected with SOD2 expression, MMP level, and Tunel staining. Hippocampal functional synaptic plasticity was assessed with long-term potentiation (LTP). In the intervention study, we overexpressed hippocampal astrocyte GLT-1 in GFAP-Cre mice. Besides, AAV-Camkllα-hM4Di-mCherry was injected to inhibit neuronal hyperexcitability in CA1 region.
Our study found T2DM but not A/S reduced GLT-1 expression in hippocampal astrocytes. Interestingly, GLT-1 deficiency alone couldn't lead to cognitive decline, but the downregulation of GLT-1 in T2DM mice obviously enhanced increased hippocampal glutamatergic neuron excitability induced by A/S. The hyperexcitability caused neuronal apoptosis and cognitive impairment. Overexpression of GLT-1 rescued postoperative cognitive dysfunction, glutamatergic neuron hyperexcitability, oxidative stress reaction, and apoptosis in hippocampus. Moreover, chemogenetic inhibition of hippocampal glutamatergic neurons reduced oxidative stress and apoptosis and alleviated postoperative cognitive dysfunction.
These findings suggest that the adult mice with type 2 diabetes are at an increased risk of developing POCD, perhaps due to the downregulation of GLT-1 in hippocampal astrocytes, which enhances increased glutamatergic neuron excitability induced by A/S and leads to oxidative stress reaction, and neuronal apoptosis.
2 型糖尿病（T2DM）与术后认知功能障碍（POCD）的风险增加有关，后者可能是由神经元过度兴奋引起的。星形胶质细胞谷氨酸转运体 1（GLT-1）在调节神经元兴奋性方面起着至关重要的作用。我们研究了 T2DM 是否会放大麻醉/手术（A/S）引起的神经元兴奋性增加，并导致年轻成年小鼠发生 POCD，如果是这样，我们还确定了这些影响是否与 GLT-1 表达有关。
通过高脂肪饮食（HFD）和注射 STZ 诱导 T2DM 模型。然后，我们使用新物体识别测试（NORT）和物体位置测试（OLT）评估 A/S 后 T2DM 小鼠的空间学习和记忆能力。使用 Western blotting 和免疫荧光分析 GLT-1 和神经元兴奋性的表达水平。通过 SOD2 表达、MMP 水平和 Tunel 染色检测氧化应激反应和神经元凋亡。通过长时程增强（LTP）评估海马功能突触可塑性。在干预研究中，我们在 GFAP-Cre 小鼠中过表达海马星形胶质细胞 GLT-1。此外，将 AAV-Camkllα-hM4Di-mCherry 注射到 CA1 区域以抑制神经元过度兴奋。
我们的研究发现，T2DM 而不是 A/S 降低了海马星形胶质细胞中的 GLT-1 表达。有趣的是，单独的 GLT-1 缺乏本身不会导致认知能力下降，但 T2DM 小鼠中 GLT-1 的下调明显增强了 A/S 引起的海马谷氨酸能神经元过度兴奋。过度兴奋导致神经元凋亡和认知障碍。GLT-1 的过表达可挽救术后认知功能障碍、海马谷氨酸能神经元过度兴奋、氧化应激反应和凋亡。此外，海马谷氨酸能神经元的化学遗传抑制可减少氧化应激和凋亡，并缓解术后认知功能障碍。
这些发现表明，2 型糖尿病成年小鼠发生 POCD 的风险增加，这可能是由于海马星形胶质细胞中 GLT-1 的下调，增强了 A/S 引起的谷氨酸能神经元过度兴奋，导致氧化应激反应和神经元凋亡。
