Department of Psychiatry and Psychology, Hainan General Hospital (Hainan Affiliated Hospital of Hainan Medical University), Haikou, Hainan 570311, China.
The Oncology Department of Hainan General Hospital (Hainan Affiliated Hospital of Hainan Medical University), First Ward, Haikou, Hainan 570311, China.
Behav Brain Res. 2025 Feb 4;477:115297. doi: 10.1016/j.bbr.2024.115297. Epub 2024 Oct 18.
This study aims to investigate the mechanism by which Histidine triad nucleotide-binding protein 1 (HINT1) promotes hippocampal neuronal apoptosis, triggering schizophrenia (SZ)-like behavior in rats. By establishing a rat SZ-like model, we assessed learning, memory, emotional response, and cognitive function through the Morris Water Maze, auditory startle response, and open field tests. HINT1 expression in the hippocampus was analyzed via RT-PCR and Western blot. We also created a HINT1 overexpression model in hippocampal neuronal cells to analyze its effects on cell proliferation and apoptosis. This analysis was conducted using the CCK-8 assay and flow cytometry, along with the quantification of apoptosis-related proteins and neurotrophic factors. Our findings indicated that the SZ-like model rats exhibited diminished learning and memory abilities, altered emotional reactions, and impaired cognitive functions, alongside a notable increase in HINT1 mRNA and protein levels. HINT1 overexpression was observed to inhibit hippocampal neuronal cell proliferation and promote apoptosis, with an increase in the expression of pro-apoptotic proteins and a decrease in neurotrophic factors. These results suggest HINT1's role in the onset and development of SZ-like behavior through its upregulation and induction of apoptosis in hippocampal neuronal cells, underlining its potential as a therapeutic target.
本研究旨在探究组氨酸三核苷酸结合蛋白 1（HINT1）促进海马神经元凋亡的机制，从而引发大鼠类似精神分裂症（SZ）的行为。通过建立大鼠 SZ 样模型，我们通过 Morris 水迷宫、听觉惊跳反应和旷场试验评估学习、记忆、情绪反应和认知功能。通过 RT-PCR 和 Western blot 分析海马组织中 HINT1 的表达。我们还在海马神经元细胞中创建了 HINT1 过表达模型，以分析其对细胞增殖和凋亡的影响。使用 CCK-8 检测和流式细胞术进行了这一分析，并对凋亡相关蛋白和神经营养因子进行了定量。我们的研究结果表明，SZ 样模型大鼠表现出学习和记忆能力下降、情绪反应改变以及认知功能受损，同时 HINT1 mRNA 和蛋白水平显著升高。过表达 HINT1 被观察到抑制海马神经元细胞的增殖并促进凋亡，同时促凋亡蛋白的表达增加，神经营养因子的表达减少。这些结果表明，HINT1 通过上调并诱导海马神经元细胞凋亡，在 SZ 样行为的发生和发展中发挥作用，突出了其作为治疗靶点的潜力。
