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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.

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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

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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.