Selective Modulation of Axonal Sodium Channel Subtypes by 5-HT1A Receptor in Cortical Pyramidal Neuron

Cereb Cortex. 2017 Jan 1;27(1):509-521. doi: 10.1093/cercor/bhv245.


Serotonergic innervation of the prefrontal cortex (PFC) modulates neuronal activity and PFC functions. However, the cellular mechanism for serotonergic modulation of neuronal excitability remains unclear. We performed patch-clamp recording at the axon of layer-5 pyramidal neurons in rodent PFC slices. We found surprisingly that the activation of 5-HT1A receptors selectively inhibits Na+ currents obtained at the axon initial segment (AIS) but not those at the axon trunk. In addition, Na+ channel subtype NaV1.2 but not NaV1.6 at the AIS is selectively modulated by 5-HT1A receptors. Further experiments revealed that the inhibitory effect is attributable to a depolarizing shift of the activation curve and a facilitation of slow inactivation of AIS Na+ currents. Consistently, dual somatic and axonal recording and simulation results demonstrate that the activation of 5-HT1A receptors could decrease the success rate of action potential (AP) backpropagation toward the somatodendritic compartments, enhancing the segregation of axonal and dendritic activities. Together, our results reveal a selective modulation of NaV1.2 distributed at the proximal AIS region and AP backpropagation by 5-HT1A receptors, suggesting a potential mechanism for serotonergic regulation of functional polarization in the dendro-axonal axis, synaptic plasticity and PFC functions.

Keywords: 5-HT1A receptor; Nav1.2; Nav1.6; action potential; axon initial segment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Axon Initial Segment / metabolism*
  • Mice
  • Mice, Mutant Strains
  • Prefrontal Cortex / metabolism*
  • Pyramidal Cells / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Serotonin, 5-HT1A / metabolism*
  • Sodium Channels / metabolism*


  • Sodium Channels
  • Receptor, Serotonin, 5-HT1A