Data_Sheet_1_Neuronal and Astrocytic Regulations in Schizophrenia: A Computational Modelling Study.PDF

According to the tripartite synapse model, astrocytes have a modulatory effect on neuronal signal transmission. More recently, astrocyte malfunction has been associated with psychiatric diseases such as schizophrenia. Several hypotheses have been proposed on the pathological mechanisms of astrocytes in schizophrenia. For example, post-mortem examinations have revealed a reduced astrocytic density in patients with schizophrenia. Another hypothesis suggests that disease symptoms are linked to an abnormality of glutamate transmission, which is also regulated by astrocytes (glutamate hypothesis of schizophrenia). Electrophysiological findings indicate a dispute over whether the disorder causes an increase or a decrease in neuronal and astrocytic activity. Moreover, there is no consensus as to which molecular pathways and network mechanisms are altered in schizophrenia. Computational models can aid the process in finding the underlying pathological malfunctions. The effect of astrocytes on the activity of neuron-astrocyte networks has been analysed with computational models. These can reproduce experimentally observed phenomena, such as astrocytic modulation of spike and burst signalling in neuron-astrocyte networks. Using an established computational neuron-astrocyte network model, we simulate experimental data of healthy and pathological networks by using different neuronal and astrocytic parameter configurations. In our simulations, the reduction of neuronal or astrocytic cell densities yields decreased glutamate levels and a statistically significant reduction in the network activity. Amplifications of the astrocytic ATP release toward postsynaptic terminals also reduced the network activity and resulted in temporarily increased glutamate levels. In contrast, reducing either the glutamate release or re-uptake in astrocytes resulted in higher network activities. Similarly, an increase in synaptic weights of excitatory or inhibitory neurons raises the excitability of individual cells and elevates the activation level of the network. To conclude, our simulations suggest that the impairment of both neurons and astrocytes disturbs the neuronal network activity in schizophrenia.

根据三元突触模型（tripartite synapse model），星形胶质细胞（astrocytes）对神经元信号传递具有调节作用。近年来的研究表明，星形胶质细胞功能异常与精神分裂症等精神疾病密切相关。学界已针对星形胶质细胞在精神分裂症中的病理机制提出多种假说：例如，死后解剖检查显示，精神分裂症患者的大脑星形胶质细胞密度显著降低；另有假说提出，疾病症状与谷氨酸传递异常相关，而谷氨酸传递同样受星形胶质细胞调控，即精神分裂症的谷氨酸假说（glutamate hypothesis of schizophrenia）。电生理研究结果显示，学界对于该疾病会导致神经元与星形胶质细胞活动增强还是减弱仍存在争议。此外，关于精神分裂症中哪些分子通路与网络机制发生改变，目前尚未达成共识。计算模型可为探索潜在病理异常提供辅助手段。已有研究通过计算模型分析了星形胶质细胞对神经元-星形胶质细胞网络活动的影响，此类模型能够复现实验观测到的现象，例如星形胶质细胞对神经元-星形胶质细胞网络中锋电位与爆发式信号的调节作用。本研究采用已建立的神经元-星形胶质细胞网络计算模型，通过设置不同的神经元与星形胶质细胞参数配置，模拟健康与病理状态下的网络实验数据。仿真结果表明，降低神经元或星形胶质细胞的密度会导致谷氨酸水平下降，且网络活动出现统计学意义上的显著降低；增强星形胶质细胞向突触后末梢释放的ATP量，同样会抑制网络活动，并造成谷氨酸水平暂时性升高。与之相反，降低星形胶质细胞的谷氨酸释放或再摄取能力，则会提升网络活动水平。同理，提高兴奋性或抑制性神经元的突触权重，会增强单个细胞的兴奋性，进而提升整体网络的激活水平。综上，本研究的仿真结果提示，神经元与星形胶质细胞的功能损伤均会干扰精神分裂症患者的神经元网络活动。