Topoisomerase 1 inhibition reversibly impairs synaptic function
Topoisomerase 1 inhibition reversibly impairs synaptic function
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DOI：
10.1073/pnas.1413204111
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发表时间：
2014-12-02
影响因子：
11.1
通讯作者：
Zylka, Mark J.
中科院分区：
文献类型：
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作者：
Mabb, Angela M.;Kullmann, Paul H. M.;Zylka, Mark J.
拓扑替康是一种拓扑异构酶1(TOP1)抑制剂，用于治疗各种形式的癌症。我们最近发现Topotecan减少了多个长基因的表达，包括许多与突触和自闭症相关的神经元基因。然而，拓扑替康是否会改变突触蛋白水平和突触功能目前尚不清楚。在这里，我们报道了在原代皮质神经元中，拓扑替康耗尽了由超长基因编码的突触蛋白，包括neuresin-1，Neuroigin-1，cntnap2，和GABA(A)beta 3。拓扑替康还抑制了自发的网络活动，而不影响静息膜电位，动作电位阈值，或神经元的健康。拓扑替康通过突触前和突触后机制强烈抑制抑制性神经传递，并减少兴奋性神经传递。药物洗脱对突触蛋白水平和抑制性神经传递的影响是完全可逆的。总而言之，我们的发现表明，TOP1控制着多种突触蛋白的水平，是正常的兴奋性和抑制性突触传递所必需的。
Topotecan is a topoisomerase 1 (TOP1) inhibitor that is used to treat various forms of cancer. We recently found that topotecan reduces the expression of multiple long genes, including many neuronal genes linked to synapses and autism. However, whether topotecan alters synaptic protein levels and synapse function is currently unknown. Here we report that in primary cortical neurons, topotecan depleted synaptic proteins that are encoded by extremely long genes, including Neurexin-1, Neuroligin-1, Cntnap2, and GABA(A)beta 3. Topotecan also suppressed spontaneous network activity without affecting resting membrane potential, action potential threshold, or neuron health. Topotecan strongly suppressed inhibitory neurotransmission via pre- and postsynaptic mechanisms and reduced excitatory neurotransmission. The effects on synaptic protein levels and inhibitory neurotransmission were fully reversible upon drug washout. Collectively, our findings suggest that TOP1 controls the levels of multiple synaptic proteins and is required for normal excitatory and inhibitory synaptic transmission.