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Topoisomerase 1 inhibition reversibly impairs synaptic function

Angela M Mabb1, Paul H M Kullmann1, Margaret A Twomey1

  • 1Department 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.

Proceedings of the National Academy of Sciences of the United States of America
|November 19, 2014
PubMed

Insights

Topoisomerase 1 (TOP1) inhibition by topotecan reduces synaptic proteins and impairs neuronal network activity. These effects on synapse function and protein levels are reversible, suggesting TOP1

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Pharmacology

Background:

  • Topotecan is a topoisomerase 1 (TOP1) inhibitor used in cancer therapy.
  • Previous research indicated topotecan reduces expression of long genes, including neuronal genes associated with synapses and autism.
  • The impact of topotecan on synaptic protein levels and synapse function remained uninvestigated.

Purpose of the Study:

  • To investigate the effects of topotecan on synaptic protein levels in primary cortical neurons.
  • To determine whether topotecan alters synaptic function, including excitatory and inhibitory neurotransmission.
  • To assess the reversibility of topotecan-induced changes in synaptic protein levels and function.

Main Methods:

  • Treatment of primary cortical neurons with topotecan.
  • Measurement of synaptic protein levels (Neurexin-1, Neuroligin-1, Cntnap2, GABA(A)β3).
  • Electrophysiological recordings to assess spontaneous network activity, resting membrane potential, action potential threshold, and neurotransmission.
  • Evaluation of reversibility upon drug washout.

Main Results:

  • Topotecan depleted synaptic proteins encoded by extremely long genes, including Neurexin-1, Neuroligin-1, Cntnap2, and GABA(A)β3.
  • Topotecan suppressed spontaneous network activity without affecting neuron health or basic electrophysiological properties.
  • Both inhibitory and excitatory neurotransmission were significantly reduced by topotecan.
  • The observed effects on synaptic proteins and inhibitory neurotransmission were fully reversible after drug removal.

Conclusions:

  • Topoisomerase 1 (TOP1) plays a critical role in regulating the expression of multiple synaptic proteins.
  • TOP1 activity is essential for normal excitatory and inhibitory synaptic transmission.
  • Topotecan's impact on synaptic function is reversible, suggesting potential therapeutic implications.
Keywords:
synapsetopoisomerasetranscription

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