Oral Presentation 2014 International Biophysics Congress

pH modulation of neuronal excitability involves a pyramidal cell axon initial segment NaV1.2 channel specific mechanism (#38)

Steven Petrou 1 , Robert Hatch 1 , David Kaplan 1 , Megan Smart 1 , Christopher Reid 1
  1. The Florey Institute, Parkville, VIC, Australia

Modulation of brain pH is known to alter neuronal excitability with acidosis causing excitation and alkalosis producing an inhibitory effect. The precise mechanism underlying this physiological important process is unknown. Using a seizure model we show how pH modulation can reduce susceptibility and occurrence of seizures and then go on to show at the neuronal network scale that acid pH changes can profoundly reduce excitability. To further investigate the neuronal mechanism we undertake single neuronal patch clamp studies in brain slices and provide evidence that while acidic shifts produce a marked decrease in action potential firing in excitatory pyramidal neurons the same pH shift has no impact on firing in inhibitory interneurons. Analysis of axon initial segment (AIS) voltage dynamics showed a significant change exclusively in pyramidal neurons suggesting an AIS mechanism. Consistent with the lack of effect on firing there was no significant alteration in interneuron AIS function after acidic pH shifts. NaV1.2 sodium channel alpha subunits are preferentially expressed in the AIS of pyramidal neurons while NaV1.1 is seen mostly in AIS of inhibitory interneurons. We tested the idea of a subunit specific pH mechanism by heterologous expression of NaV1.1 and NaV1.2 in HEK293 cells. Whole cell voltage clamp revealed that acidity accelerated the entry of NaV1.2 into slow inactivation similar to the action of carbamazepine while no significant effect was seen on NaV1.1. pH is an arbiter of neuronal excitability important in normal and disease physiology and here we reveal molecular and neuronal subtype mechanisms that underlie this homeostatic mechanism in the brain.