Topoisomerase 1 inhibition reversibly impairs synaptic function

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / drug effects
  • Animals
  • Calcium-Binding Proteins
  • Cell Adhesion Molecules, Neuronal / metabolism
  • Cells, Cultured
  • Cerebral Cortex / cytology
  • DNA Topoisomerases, Type I / metabolism*
  • Excitatory Postsynaptic Potentials / drug effects*
  • Excitatory Postsynaptic Potentials / physiology
  • Female
  • Immunoblotting
  • Mice, Inbred C57BL
  • Microscopy, Fluorescence
  • Neural Cell Adhesion Molecules / metabolism
  • Neurons / drug effects*
  • Neurons / metabolism
  • Neurons / physiology
  • Patch-Clamp Techniques
  • Synapses / drug effects*
  • Synapses / physiology
  • Topoisomerase I Inhibitors / pharmacology
  • Topotecan / pharmacology*

Substances

  • Calcium-Binding Proteins
  • Cell Adhesion Molecules, Neuronal
  • Neural Cell Adhesion Molecules
  • Nrxn1 protein, mouse
  • Topoisomerase I Inhibitors
  • neuroligin 1
  • Topotecan
  • DNA Topoisomerases, Type I