Causes and Consequences of Hyperexcitation in Central Clock Neurons

Casey O. Diekman, Mino D.C. Belle, Robert P. Irwin, Charles N. Allen, Hugh D. Piggins, Daniel B. Forger

Research output: Contribution to journalArticle

26 Scopus citations

Abstract

Hyperexcited states, including depolarization block and depolarized low amplitude membrane oscillations (DLAMOs), have been observed in neurons of the suprachiasmatic nuclei (SCN), the site of the central mammalian circadian (∼24-hour) clock. The causes and consequences of this hyperexcitation have not yet been determined. Here, we explore how individual ionic currents contribute to these hyperexcited states, and how hyperexcitation can then influence molecular circadian timekeeping within SCN neurons. We developed a mathematical model of the electrical activity of SCN neurons, and experimentally verified its prediction that DLAMOs depend on post-synaptic L-type calcium current. The model predicts that hyperexcited states cause high intracellular calcium concentrations, which could trigger transcription of clock genes. The model also predicts that circadian control of certain ionic currents can induce hyperexcited states. Putting it all together into an integrative model, we show how membrane potential and calcium concentration provide a fast feedback that can enhance rhythmicity of the intracellular circadian clock. This work puts forward a novel role for electrical activity in circadian timekeeping, and suggests that hyperexcited states provide a general mechanism for linking membrane electrical dynamics to transcription activation in the nucleus.

Original languageEnglish (US)
Article numbere1003196
JournalPLoS computational biology
Volume9
Issue number8
DOIs
StatePublished - Aug 2013

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Modeling and Simulation
  • Ecology
  • Molecular Biology
  • Genetics
  • Cellular and Molecular Neuroscience
  • Computational Theory and Mathematics

Fingerprint Dive into the research topics of 'Causes and Consequences of Hyperexcitation in Central Clock Neurons'. Together they form a unique fingerprint.

  • Cite this

    Diekman, C. O., Belle, M. D. C., Irwin, R. P., Allen, C. N., Piggins, H. D., & Forger, D. B. (2013). Causes and Consequences of Hyperexcitation in Central Clock Neurons. PLoS computational biology, 9(8), [e1003196]. https://doi.org/10.1371/journal.pcbi.1003196