糖原合酶激酶3β对颅脑放射诱发的突触可塑性和认知功能损害的影响及其机制

Cranial irradiation is widely used to treat patients with primary or metastatic central nervous system tumors recently. The most common long-term complications of cranial irradiation include various degrees of cognitive dysfunction. Glycogen synthase kinase 3β (GSK-3β) is highly expressed in the mammalian brain and is closely associated with synaptic plasticity and hippocampus-dependent learning and memory impairment. Recent studies demonstrated that inhibition of GSK-3β reslulted in significant protection from radiation-induced apoptosis in HT-22 neurons in vitro. We found that the GSK-3β activity was significantly activated in the hippocampus of mice following cranial irradiation. However, the role of GSK-3β in cranial radiation-induced synaptic plasticity and cognitive impairment in mice hippocampus was poorly understood. In present study, we will clarify whether the expression of the presynaptic protein Synapsin I is down-regulated and the LTP is inhibited via GSK-3β activition induced by cranial radiation. We will investigate whether the cognitive dysfunction induced by cranial radiation can be reversed by inhibition of GSK-3β. The project will provide a effective molecular target for early prevention of learning and memory dysfunction induced by cranial irradiation, and explore the possible mechanism how GSK-3β inhibitors protect the learning and memory abilities.

颅脑放射目前已广泛应用于原发性或转移性颅内肿瘤的治疗，其最常见远期并发症为不同程度的认知功能障碍。糖原合酶激酶3β（GSK-3β）在哺乳动物脑组织中高表达，与神经元突触可塑性及海马依赖性的学习记忆障碍密切相关。研究表明抑制GSK-3β活性能明显保护放射诱发的体外培养的HT-22海马神经元凋亡，我们前期研究发现颅脑放射小鼠海马内GSK-3β的活性明显激活，但GSK-3β在全脑放射后小鼠海马神经元突触可塑性及学习记忆障碍中的作用仍不清楚。本项目拟阐明全脑放射能否通过激活成年小鼠海马组织GSK-3β活性，进而抑制突触前重要蛋白质synapsin I (SynI)的表达而负向调控LTP并引起认知功能障碍，而抑制GSK-3β能保护全脑放射后小鼠认知功能。该研究将为颅脑放疗患者认知障碍的早期防治提供有效的分子靶点，并将阐明GSK-3β抑制剂保护其学习记忆功能的可能机制。

目前颅脑放射相关认知功能损害的发病机制尚未完全明确。糖原合酶激酶3β（GSK-3β）在哺乳动物脑组织中高表达，与神经元突触可塑性及海马依赖性的学习记忆障碍密切相关。研究表明抑制GSK-3β活性能明显保护放射诱发的体外培养的HT-22海马神经元凋亡，我们前期研究发现颅脑放射小鼠海马内GSK-3β的活性明显激活，但GSK-3β在全脑放射后小鼠海马神经元突触可塑性及学习记忆障碍中的作用仍不清楚。本项目发现：（1）全脑放射能通过激活成年小鼠海马组织GSK-3β活性，负向调控LTP并引起认知功能障碍；（2）抑制GSK-3β能保护全脑放射后小鼠海马神经元突触可塑性，从而增强海马区长时程增强，保护认知功能。该项目的研究结果可为将来颅脑放疗患者认知障碍的早期防治提供有效的分子靶点和新策略。