Brask Johan, Kristensson Krister, Hill Russell H
Department of Neuroscience, Karolinska Institutet, Retzius väg 8, SE-17177, Stockholm, Sweden.
Eur J Neurosci. 2004 Jun;19(12):3193-201. doi: 10.1111/j.0953-816X.2004.03445.x.
Certain disorders of the nervous system may have their origin in disturbances in the development of synaptic connections and network structure that may not become overt until later in life. As inflammatory cytokines can influence synaptic activity in neuronal cultures, we analysed whether cytokine exposure during synaptogenesis can lead to imbalances in a neuronal network. Short-term application of interferon-gamma (IFN-gamma), but not tumour necrosis factor-alpha, during peak synaptogenesis (but not before or after) in Sprague-Dawley rat hippocampal cultures, caused both a decrease in the frequency of spontaneous excitatory postsynaptic currents (EPSCs) and an increase in the frequency of spontaneous inhibitory postsynaptic currents (IPSCs). These effects were only detected in recordings made weeks later. This was not due to a depression of glutamatergic synapses or to a change in the relative number of neurons containing glutamic acid decarboxylase (GAD). There was an increase in the average amplitude of miniature IPSCs, and in GAD-expressing neurons the amplitude of miniature EPSCs were larger as well as the responses to glutamate. This indicates that IFN-gamma-treatment induced increased inhibition via postsynaptic changes. These effects of IFN-gamma treatment were not observed when neuronal nitric oxide synthase was inhibited. Our study therefore shows that exposure to IFN-gamma during a restricted period of development, which coincides with the peak of excitatory synaptogenesis, can cause progressive changes in synaptic activity in the network. Thus, cytokine exposure at a critical period of development may constitute a 'hit-and-run' mechanism for certain nervous system disorders that become manifest after a latency period.
某些神经系统疾病可能起源于突触连接和网络结构发育过程中的紊乱，这些紊乱可能直到生命后期才会显现出来。由于炎性细胞因子可影响神经元培养物中的突触活性，我们分析了在突触发生过程中暴露于细胞因子是否会导致神经网络失衡。在Sprague-Dawley大鼠海马培养物突触发生高峰期（而非之前或之后）短期应用γ-干扰素（IFN-γ），而非肿瘤坏死因子-α，导致自发兴奋性突触后电流（EPSCs）频率降低，同时自发抑制性突触后电流（IPSCs）频率增加。这些效应仅在数周后的记录中被检测到。这并非由于谷氨酸能突触的抑制或含谷氨酸脱羧酶（GAD）的神经元相对数量的改变。微小IPSCs的平均幅度增加，在表达GAD的神经元中，微小EPSCs的幅度更大，对谷氨酸的反应也更大。这表明IFN-γ处理通过突触后变化诱导了抑制作用增强。当神经元型一氧化氮合酶被抑制时，未观察到IFN-γ处理的这些效应。因此，我们的研究表明，在与兴奋性突触发生高峰期相吻合的发育受限时期暴露于IFN-γ，可导致网络中突触活性的渐进性变化。因此，在发育关键期暴露于细胞因子可能构成某些潜伏期后才显现的神经系统疾病的“肇事逃逸”机制。
