Molecular and functional differences in voltage-activated sodium currents between GABA projection neurons and dopamine neurons in the substantia nigra

Abstract

Ding S, Wei W, Zhou FM. Molecular and functional differences in voltage-activated sodium currents between GABA projection neurons and dopamine neurons in the substantia nigra. J Neurophysiol 106: 3019-3034, 2011. First published August 31, 2011 doi:10.1152/jn.00305.2011 in the substantia nigra pars reticulata (SNr) and dopamine projection neurons (DA neurons) in substantia nigra pars compacta (SNc) have strikingly different firing properties. SNc DA neurons fire low-frequency, long-duration spikes, whereas SNr GABA neurons fire high-frequency, short-duration spikes. Since voltage-activated sodium (Na V ) channels are critical to spike generation, the different firing properties raise the possibility that, compared with DA neurons, Na V channels in SNr GABA neurons have higher density, faster kinetics, and less cumulative inactivation. Our quantitative RT-PCR analysis on immunohistochemically identified nigral neurons indicated that mRNAs for poreforming Na V 1.1 and Na V 1.6 subunits and regulatory Na V ␤1 and Na v ␤4 subunits are more abundant in SNr GABA neurons than SNc DA neurons. These ␣-subunits and ␤-subunits are key subunits for forming Na V channels conducting the transient Na V current (I NaT ), persistent Na current (I NaP ), and resurgent Na current (I NaR ). Nucleated patch-clamp recordings showed that I NaT had a higher density, a steeper voltage-dependent activation, and a faster deactivation in SNr GABA neurons than in SNc DA neurons. I NaT also recovered more quickly from inactivation and had less cumulative inactivation in SNr GABA neurons than in SNc DA neurons. Furthermore, compared with nigral DA neurons, SNr GABA neurons had a larger I NaR and I NaP . Blockade of I NaP induced a larger hyperpolarization in SNr GABA neurons than in SNc DA neurons. Taken together, these results indicate that Na V channels expressed in fast-spiking SNr GABA neurons and slow-spiking SNc DA neurons are tailored to support their different spiking capabilities. basal ganglia; substantia nigra; transient sodium current; persistent sodium current; resurgent sodium current AS A KEY COMPONENT OF THE basal ganglia motor circuitry, substantia nigra (SN) is populated largely by two types of projection neurons: GABA neurons in SN pars reticulata (SNr) and dopamine (DA) neurons in SN pars compacta (SNc) and also in SNr (Bolam et al. 2000;Deniau et al. 2007; GonzalezHernandez and Rodriguez, 2000;Nelson et al. 1996; Parent et al. 2000). SNr GABA neurons and SNc DA neurons have strikingly different firing properties. SNr GABA neurons fire high-frequency, brief action potentials (Atherton et al. 2005; Zhou et al. 2006), whereas SNc DA neurons fire low-frequency, long-duration spikes (Hyland et al. 2002; Zhou et al. 2006), indicating potential differences in voltage-gated potassium (K v ) and sodium (Na V ) channels in these two cell types (Ding et al. 2011;Seutin and Engel 2010). Indeed, our laboratory's recent study showed that a K v 3-like current is essential to the sustained high-frequency firing in SNr GABA neurons (D...

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

“…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.…”

“…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.…”

“…B: slow inactivation of the sodium current summates when repeated 3-ms depolarizing pulses to 0 mV are applied to the model at 100-ms intervals from a holding potential of Ϫ70 mV. To match Ding et al (2011), g Na was set to 9.12 nS. C: the time course of the activation variable n (gray curves) during the simulation shown in D1 was fit to an instantaneous polynomial function [f(h), black] of the inactivation variable h. D1: pacemaking in full 5-dimensional (5D) model at applied current (I app ) ϭ 0 A/cm 2 .…”

Robust presynaptic serotonin 5-HT1B receptor inhibition of the striatonigral output and its sensitization by chronic fluoxetine treatment

“…The main neuron type in the SNr is the GABA projection neurons that fire spontaneously around 10 Hz under in vitro conditions (Atherton and Bevan 2005;Ding et al 2011aDing et al , 2011b; Zhou and Lee 2011). The SNr also contains sparse dopamine neurons that fire spontaneously around 1.5 Hz under similar in vitro conditions (Connelly et al 2010;Ding et al 2011aDing et al , 2011bZhou et al 2006).…”

“…The SNr also contains sparse dopamine neurons that fire spontaneously around 1.5 Hz under similar in vitro conditions (Connelly et al 2010;Ding et al 2011aDing et al , 2011bZhou et al 2006). Therefore, we first briefly recorded action potentials of neurons in SNr in a cell-attached mode in our angular sagittal brain slices (Fig.…”