Previous studies using pharmacological methods suggest that subthreshold sodium currents are critical for rhythmical burst generation in mesencephalic trigeminal neurons (Mes V). In this study, we characterized transient ( INaT), persistent ( INaP), and resurgent ( Ires) sodium currents in Nav1.6-null mice ( med mouse, Nav1.6−/−) lacking expression of the sodium channel gene Scn8a. We found that peak transient, persistent, and resurgent sodium currents from med (Nav1.6−/−) mice were reduced by 18, 39, and 76% relative to their wild-type (Nav1.6+/+) littermates, respectively. Current clamp recordings indicated that, in response to sinusoidal constant amplitude current (ZAP function), all neurons exhibited membrane resonance. However, Mes V neurons from med mice had reduced peak amplitudes in the impedance-frequency relationship (resonant Q-value) and attenuated subthreshold oscillations despite the similar passive membrane properties compared with wild-type littermates. The spike frequency-current relationship exhibited reduced instantaneous discharge frequencies and spike block at low stimulus currents and seldom showed maintained spike discharge throughout the stimulus in the majority of med neurons compared with wild-type neurons. Importantly, med neurons never exhibited maintained stimulus-induced rhythmical burst discharge unlike those of wild-type littermates. The data showed that subthreshold sodium currents are critical determinants of Mes V electrogenesis and burst generation and suggest a role for resurgent sodium currents in control of spike discharge.
Increased Resurgent Sodium Currents in Nav1.8 Contribute to Nociceptive Sensory Neuron Hyperexcitability Associated with Peripheral Neuropathies
