Heat opens axon initial segment sodium channels: a febrile seizure mechanism?

Ann Neurol. 2009 Aug;66(2):219-26. doi: 10.1002/ana.21712.


Objective: A number of hypotheses have been put forward as to why humans respond to fever by seizing. The current leading hypotheses are that respiratory alkalosis produces an as yet unidentified change in neural excitability or that inflammatory mediators potentiate excitatory synaptic transmission. However, it is well known that ion channel gating rates increase with increased temperature. Furthermore, skeletal and cardiac sodium channel activation can be temperature sensitive in some situations. We measured the temperature sensitivity of the brain sodium channel, Na(V)1.2, to determine whether febrile temperatures might produce a direct increase in neuronal excitability.

Methods: The effect of temperature on Na(V)1.2 electrophysiological properties was measured in a transfected mammalian cell line. The subcellular location of Na(V)1.2 in the mouse brain was ascertained using antibodies against Na(V)1.2 and ankyrin-G. Computer simulation of a hippocampal granule cell model was used to predict the effect of temperature on action potential firing.

Results: As well as the expected increase in gating rates, the voltage dependence of activation became 7.6 mV more negative when the temperature was increased from 37 degrees C to 41 degrees C. Na(V)1.2 was localized to the axon initial segment in hippocampal and cortical neurons. Computer simulation showed that increased gating rates and the more negative activation dramatically increase neuronal excitability.

Interpretation: The direct effect of heat on ion channels localized to the site of action potential initiation potentially causes a profound increase in neuronal excitability. This is likely to contribute to febrile seizure genesis.

MeSH terms

  • Action Potentials / physiology
  • Aging
  • Animals
  • Animals, Newborn
  • Ankyrins / metabolism
  • Axons / physiology*
  • Cell Line
  • Cerebral Cortex / growth & development
  • Cerebral Cortex / physiopathology
  • Computer Simulation
  • Hippocampus / growth & development
  • Hippocampus / physiopathology
  • Hot Temperature*
  • Humans
  • Membrane Potentials / physiology
  • Mice
  • Mice, Inbred C57BL
  • NAV1.2 Voltage-Gated Sodium Channel
  • Nerve Tissue Proteins / metabolism*
  • Neurons / physiology*
  • Seizures, Febrile / physiopathology*
  • Sodium Channels / metabolism*
  • Transfection


  • Ank3 protein, mouse
  • Ankyrins
  • NAV1.2 Voltage-Gated Sodium Channel
  • Nerve Tissue Proteins
  • SCN2A protein, human
  • Scn2a protein, mouse
  • Sodium Channels