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Proc Natl Acad Sci U S A. 2014 Dec 2;111(48):17290-5. doi: 10.1073/pnas.1413204111. Epub 2014 Nov 17.

Topoisomerase 1 inhibition reversibly impairs synaptic function.

Author information

1
Department of Cell Biology and Physiology, University of North Carolina Neuroscience Center, Carolina Institute for Developmental Disabilities, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599.
2
Department of Cell Biology and Physiology, University of North Carolina Neuroscience Center, Carolina Institute for Developmental Disabilities, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 benjamin_philpot@med.unc.edu zylka@med.unc.edu.

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.

KEYWORDS:

synapse; topoisomerase; transcription

PMID:
25404338
PMCID:
PMC4260568
DOI:
10.1073/pnas.1413204111
[Indexed for MEDLINE]
Free PMC Article

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