Topoisomerase 1 inhibition reversibly impairs synaptic function
| Autor: | Margaret A. Twomey, Jayalakshmi Miriyala, Mark J. Zylka, Angela M. Mabb, Benjamin D. Philpot, Paul H. M. Kullmann |
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| Rok vydání: | 2014 |
| Předmět: |
Patch-Clamp Techniques
endocrine system diseases Cell Adhesion Molecules Neuronal Immunoblotting Action Potentials Biology Neurotransmission Inhibitory postsynaptic potential Synapse Postsynaptic potential medicine Animals Neural Cell Adhesion Molecules Cells Cultured Cerebral Cortex Neurons Multidisciplinary Calcium-Binding Proteins Excitatory Postsynaptic Potentials Biological Sciences Cell biology Mice Inbred C57BL Synaptic fatigue DNA Topoisomerases Type I Microscopy Fluorescence Synapses Synaptic plasticity Excitatory postsynaptic potential Female Topotecan Topoisomerase I Inhibitors medicine.drug |
| Zdroj: | Proceedings of the National Academy of Sciences. 111:17290-17295 |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | 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)β3. 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. |
| Databáze: | OpenAIRE |
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