Differences in Na⁺Conductance Density and Na⁺Channel Functional Properties Between Dopamine and GABA Neurons of the Rat Substantia Nigra

Abstract

Dopamine (DA) neurons and GABA neurons of the substantia nigra (SN) promote distinct functions in the control of movement and have different firing properties and action potential (AP) waveforms. APs recorded from DA and GABA neurons differed in amplitude, maximal rate of rise, and duration. In addition, the threshold potential for APs was higher in DA neurons than in GABA neurons. The activation of voltage-gated Na(+) channels accounts largely for these differences as the application of a low concentration of the voltage-gated Na(+) channel blocker TTX had an effect on all of these parameters. We have examined functional properties of somatic Na(+) channels in nucleated patches isolated from DA and GABA neurons. Peak amplitudes of macroscopic Na(+) currents were smaller in DA neurons in comparison to those in GABA neurons. The mean peak Na(+) conductance density was 24.5 pS microm(-2) in DA neurons and almost twice as large, 41.6 pS microm(-2), in GABA neurons. The voltage dependence of Na(+) channel activation was not different between the two types of SN neurons. Na(+) channels in DA and GABA neurons, however, differed in the voltage dependence of inactivation, the mean mid-point potential of steady-state inactivation curve being more positive in DA neurons than in GABA neurons. The results suggest that specific Na(+) channel gating properties and Na(+) conductance densities in the somatic membrane of SN neurons may have consequences on synaptic signal integration in the soma of both types of neurons and on somatodendritic release of dopamine by DA neurons.

Mathematical analysis of depolarization block mediated by slow inactivation of fast sodium channels in midbrain dopamine neurons

“…The relatively hyperpolarized halfinactivation point and the relatively steep voltage dependence of the steady-state value of h s are consistent with Fernandez and White (2010) and Migliore et al (1999). We confirmed that the addition of slow inactivation did not compromise the fit to the experimental data by simulating the voltage-clamp protocols described in Seutin and Engel (2010). The voltage-clamp data were obtained with nucleated patches from dopamine neurons in the substantia nigra and previously published by others.…”

“…During steps to depolarized membrane potentials (Ͼ Ϫ30 mV), we hypothesize that a second slow component of sodium channel inactivation is present but cannot be observed because it is occluded by the faster entry into the fast inactivated state, and therefore inactivation has a monoexponential onset. During recovery from inactivation, however, a biexponential recovery is evident, which indicates that inactivation has a fast and a slow component (Ding et al 2011;Seutin and Engel 2010). Although variable fractions of the channels recorded in nucleated patches in these studies were reported to exhibit slow inactivation, in our model all channels exhibit slow inactivation.…”

“…The dynamics of the activation (m) and fast inactivation (h) of the Na current were taken directly from Ji et al (2012) and Tucker et al (2012), because this description faithfully reproduces the peak currents observed during the single-step voltage-clamp experiments described by Seutin and Engel (2010) and shown in Fig. 1A.…”

“…Previous models (Drion et al 2011;Kuznetsova et al 2010;Oster and Gutkin 2011) do not capture critical aspects of the firing rate limitation and how it is circumvented. Therefore we examined depolarization block in a simple model that faithfully reproduces the sodium current measured in these neurons (Seutin and Engel 2010) and also in a model with an additional slow component of sodium channel inactivation, recently observed in these neurons (Ding et al 2011). We discovered that these models entered into depolarization block in two different ways and experimentally demonstrated that a dopamine neuron can enter into depolarization block either way, depending upon the experimental conditions.…”

Selective Gating of Neuronal Activity by Intrinsic Properties in Distinct Motor Rhythms

“…The availability of Na ϩ channels is often measured using the maximal rate of rise of spikes (Seutin and Engel, 2010), and I Na ϩ inactivation can be detected as a reduction in this maximal rate of rise. Therefore, I measured the maximal rate of rise in just-abovethreshold spikes as an indirect measurement for I Na ϩ inactivation.…”