@article{Vestibular:4870,
      recid = {4870},
      author = {Baeza-Loya, Selina},
      title = {Sodium Current Diversity and Spike Timing in Vestibular  Ganglion Neurons},
      publisher = {University of Chicago},
      school = {Ph.D.},
      address = {2022-08},
      pages = {119},
      abstract = {The vestibular inner ear transmits head-motion information  to the brain via two populations of primary vestibular  ganglion neurons (VGNs) which differ in the regularity of  action potential (AP) timing (regular and irregular) and  represent rate and temporal encoding, respectively.  Although voltage-gated sodium (NaV) currents drive the  rising phase of APs, their contributions to AP waveform and  spike timing regularity in VGNs are not fully understood.  NaV currents through a given α subunit can have different  modes: they can be transient (inactivating), persistent  (noninactivating), and/or resurgent (following relief from  inactivation block). Here we consider how these NaV current  modes influence AP firing in isolated VGNs, which respond  to current injections with sustained and transient firing  patterns. These correspond to regular and irregular  spiking, respectively. Whole-cell recordings from mouse  VGNs revealed that while all had large transient NaV  currents that were blocked by 1 μM tetrodotoxin (TTX), some  also had persistent current, and a subset had resurgent  current. 
A blocker of NaV1.6 channels  (4,9-anhydro-tetrodotoxin, 4,9-ah-TTX) partially blocked  transient and eliminated persistent and resurgent currents,  indicating that a substantial portion of each flow through  NaV1.6 channels. In current clamp, 4,9-ah-TTX decreased  excitability: increasing current threshold for spiking in  all VGNs, but hyperpolarized resting membrane potential in  sustained (regular) VGNs. A sodium channel agonist  (Anemonia viridis toxin 2) had the opposite effect of  increasing excitability as measured by decreased current  threshold for spiking and increased AP rate and spiking  regularity.
We did not detect a clear relationship between  NaV conductance and firing patterns due to unexpected  variability in NaV conductance in VGN. We determined that  sustained-A firing VGNs (which respond to current  injections with tonic spike trains) have higher amplitude  APs and faster rates of depolarization relative to  transient VGNs (which fire a single spike at stimulus  onset). Using the action potential clamp technique, we  observed that sustained VGNs have less NaV current flow  during the depolarization phase of the AP, due to their  increased excitability and decreased input resistance  relative to transient VGNs and possible differences in  underlying channel kinetics. 
However, it is difficult to  experimentally distinguish the effects of these currents on  spiking because we lack methods to isolate current modes.  We therefore modified a computational conductance-based  model of VGN by adjusting and adding expressions for  transient, persistent, and resurgent NaV components with  properties based on our data. In model transient  (irregular) VGN, adding persistent and resurgent current  components had a negligible effect on firing. In model  sustained (regular) VGN, adding resurgent currents reduced  refractory periods and increased spike rate. When examining  the impact on regularity, we observed that increasing  transient current increased spiking regularity  independently of increased spike rate in all model VGNs,  while persistent and resurgent currents did not enhance  spiking regularity. 
In summary, transient NaV current  increases excitability and spike timing regularity by  counterbalancing inexcitability driven by increased low  voltage-activated potassium. Resurgent NaV current  facilitates excitability in regularly firing VGNs, but do  not impact regularity.
},
      url = {http://knowledge.uchicago.edu/record/4870},
      doi = {https://doi.org/10.6082/uchicago.4870},
}