Causes and Consequences of Hyperexcitation in Central Clock Neurons

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

Research output: Contribution to journalArticle

26 Citations (Scopus)

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

Fingerprint

Suprachiasmatic Nucleus
Neurons
Nucleus
Clocks
Neuron
neurons
Calcium
membrane
Membranes
calcium
Membrane
oscillation
Transcription
24 hour clock
Circadian Clocks
Periodicity
transcriptional activation
Oscillation
membrane potential
Predict

ASJC Scopus subject areas

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

Cite this

Diekman, C. O., Belle, M. D. C., Irwin, R. P., Allen, C., 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

Causes and Consequences of Hyperexcitation in Central Clock Neurons. / Diekman, Casey O.; Belle, Mino D C; Irwin, Robert P.; Allen, Charles; Piggins, Hugh D.; Forger, Daniel B.

In: PLoS Computational Biology, Vol. 9, No. 8, e1003196, 08.2013.

Research output: Contribution to journalArticle

Diekman, CO, Belle, MDC, Irwin, RP, Allen, C, Piggins, HD & Forger, DB 2013, 'Causes and Consequences of Hyperexcitation in Central Clock Neurons', PLoS Computational Biology, vol. 9, no. 8, e1003196. https://doi.org/10.1371/journal.pcbi.1003196
Diekman, Casey O. ; Belle, Mino D C ; Irwin, Robert P. ; Allen, Charles ; Piggins, Hugh D. ; Forger, Daniel B. / Causes and Consequences of Hyperexcitation in Central Clock Neurons. In: PLoS Computational Biology. 2013 ; Vol. 9, No. 8.
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