精神分裂症易感基因Tmem108在前额叶皮层髓鞘化与认知功能中的作用

In the central nervous system (CNS), myelin is an insulation structure that surrounds the axons of nerve cells, formed by the plasma membrane of oligodendrocytes. This ensheathment of axons is to increase action potential conduction velocity, which is essential for the proper functioning of CNS. Previous studies showed myelination deficits in prefrontal cortex (PFC) could impair higher cognitive functions. However, the underlying mechanism is unclear. Previously, we found transmembrane protein 108 (Tmem108), a schizophrenia susceptibility gene, is expressed highly in PFC during the critical period of myelination. Tmem108-deficient mice displayed impair spatial working memory and less myelin basic protein (MBP) was found in the PFC. These results implicate that Tmem108 may play an important role in PFC myelination and cognitive functions. In this study, first, we will use Tmem108-deficient mice to illuminate whether and how Tmem108 affects myelination in the PFC, and what the underlying cellular and molecular mechanism is; secondly, we will investigate whether myelin level can be rescued in the PFC when overexpressing Tmem108 in demyelination model mice, to study the role of Tmem108 in remyelination; finally, we will use behavioral paradigms to detect whether Tmem108 plays a role in PFC cognitive functions. This study will not only enrich the research on pathophysiological mechanisms in schizophrenia, but also provide potential therapeutic targets for myelin deficit-related nervous disorders.

在中枢神经系统，髓鞘由少突胶质细胞产生，是包绕在神经元轴突上的一种多层绝缘膜结构。轴突髓鞘化有利于动作电位的快速传导，确保中枢神经系统功能的正常执行。研究表明前额叶髓鞘缺陷可导致认知功能障碍，但具体分子机制尚不清楚。我们前期工作发现，精神分裂症易感基因Tmem108在前额叶髓鞘发育关键时期具有高表达，且Tmem108缺失小鼠空间工作记忆能力受损，前额叶髓鞘特异性蛋白MBP表达量减少。这些结果提示，Tmem108可能在前额叶髓鞘化及认知功能中有重要作用。本项目拟应用Tmem108敲除小鼠，研究Tmem108在前额叶髓鞘发育中的作用及其分子机制；构建小鼠脱髓鞘模型，研究前额叶Tmem108表达上调能否促进髓鞘的再生；通过行为学方法，观察Tmem108在前额叶认知功能实施中的重要性。本项目对进一步理解精神分裂症的病理机制具有重要理论意义，为发掘髓鞘缺陷相关神经疾病的潜在治疗靶点提供了理论依据。

在中枢神经系统中，髓鞘是少突胶质细胞细胞膜包绕轴突形成的一种多层绝缘膜结构。髓鞘缺陷会使得中枢神经系统功能异常。现今髓鞘研究多集中于大脑白质，灰质髓鞘研究较少。前额叶皮层是最高级别的联合皮层也是髓鞘化最晚完成的脑区。前额叶皮层髓鞘缺陷会导致认知功能出现障碍。精神分裂症更与前额叶皮层髓鞘缺陷密切相关，但具体机制并不清楚。我们前期工作发现，精神分裂症易感基因Tmem108在新生的少突胶质细胞高表达，且在前额叶皮层髓鞘发育的关键时期，Tmem108蛋白表达水平也快速升高。本项目拟研究Tmem108在前额叶皮层髓鞘发育中的作用以及敲除Tmem108对前额叶皮层相关认知功能的影响。我们的实验结果表明：在小鼠髓鞘发育的关键时期，敲除Tmem108小鼠前额叶皮层髓鞘特异性表达蛋白的表达水平下降，包裹轴突髓鞘厚度减少，成熟少突胶质细胞数量也减少；脱髓鞘模型中，敲除Tmem108小鼠前额叶皮层再生能力减弱；敲除Tmem108的小鼠前额叶皮层相关的认知功能受损，具体表现为：空间学习和记忆能力受损、空间反转能力受损、社交能力受损。这些结果提示，精神分裂症易感基因Tmem108参与前额叶皮层髓鞘形成过程，敲除Tmem108会减前额叶皮层少突胶质细胞数量，从而使髓鞘发育受损，髓鞘再生异常，及前额叶皮层相关的认知功能也受损。这对进一步理解精神分裂症的病理机制具有重要理论意义，也为发掘髓鞘缺陷相关神经疾病的潜在治疗靶点提供了重要的理论依据。