Topoisomerase 1 inhibition reversibly impairs synaptic function.
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.
['Mabb|Angela M|AM|', 'Kullmann|Paul H M|PH|', 'Twomey|Margaret A|MA|', 'Miriyala|Jayalakshmi|J|', 'Philpot|Benjamin D|BD|', 'Zylka|Mark J|MJ|']
D000200:Action Potentials D000818:Animals D002135:Calcium-Binding Proteins D015816:Cell Adhesion Molecules, Neuronal D002478:Cells, Cultured D002540:Cerebral Cortex D004264:DNA Topoisomerases, Type I D019706:Excitatory Postsynaptic Potentials D005260:Female D015151:Immunoblotting D008810:Mice, Inbred C57BL D008856:Microscopy, Fluorescence D019006:Neural Cell Adhesion Molecules D009474:Neurons D018408:Patch-Clamp Techniques D013569:Synapses D059004:Topoisomerase I Inhibitors D019772:Topotecan
topoisomerase synapse transcription