Topoisomerase 1 inhibition reversibly impairs synaptic function
Year: 2014
Type: article
Abstract: 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.
Institution: University of North Carolina at Chapel Hill
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
Funders: Angelman Syndrome Foundation, Simons Foundation Autism Research Initiative, National Institutes of Health, National Institute of Mental Health, National Institute of Neurological Disorders and Stroke, National Institute of Environmental Health Sciences, National Center for Chronic Disease Prevention and Health Promotion, Eunice Kennedy Shriver National Institute of Child Health and Human Development
OpenAlex ID: W1993676097