Ionic Mechanisms Underlying Autonomous Action Potential Generation in the Somata and Dendrites of GABAergic Substantia Nigra Pars Reticulata NeuronsIn Vitro

Abstract

Through their repetitive discharge, GABAergic neurons of the substantia nigra pars reticulata (SNr) tonically inhibit the target nuclei of the basal ganglia and the dopamine neurons of the midbrain. As the repetitive firing of SNr neurons persists in vitro, perforated, whole-cell and cell-attached patch-clamp recordings were made from rat brain slices to determine the mechanisms underlying this activity. The spontaneous activity of SNr neurons was not perturbed by the blockade of fast synaptic transmission, demonstrating that it was autonomous in nature. A subthreshold, slowly inactivating, voltage-dependent, tetrodotoxin (TTX)-sensitive Na ϩ current and a TTX-insensitive inward current that was mediated in part by Na ϩ were responsible for depolarization to action potential (AP) threshold. An apamin-sensitive spike afterhyperpolarization mediated by small-conductance Ca 2ϩ -dependent K ϩ (SK) channels was critical for the precision of autonomous activity. SK channels were activated, in part, by Ca 2ϩ flowing through -conotoxin GVIA-sensitive, class 2.2 voltage-dependent Ca 2ϩ channels. Although Cs ϩ /ZD7288 (4-ethylphenylamino-1,2-dimethyl-6-methylaminopyrimidinium chloride)-sensitive hyperpolarization-activated currents were also observed in SNr neurons, they were activated at voltages that were in general more hyperpolarized than those associated with autonomous activity. Simultaneous somatic and dendritic recordings revealed that autonomously generated APs were observed first at the soma before propagating into dendrites up to 120 m from the somatic recording site. Backpropagation of autonomously generated APs was reliable with no observable incidence of failure. Together, these data suggest that the resting inhibitory output of the basal ganglia relies, in large part, on the intrinsic firing properties of the neurons that convey this signal.

Effects of Drugs of Abuse on Putative Rostromedial Tegmental Neurons, Inhibitory Afferents to Midbrain Dopamine Cells

“…The estimated resting membrane potential was À44.5±9.9 mV, and putative RMTg cells fired short-duration spikes (mean width at threshold: 1.77 ± 0.01 ms), whose amplitude and input resistance were 65.0 ± 0.8 mV and 304 ± 37 MO, respectively. These electrophysiological features are similar to those described for GABA neurons of the neighbor pars reticulata of the substantia nigra recorded under the same conditions (Atherton and Bevan, 2005). EPSCs were evoked by repetitively stimulating the afferents (duration 50 ms, frequency 0.1 Hz, intensity 0.01À0.30 mA) with a stimulating electrode that was placed rostro-laterally (B150 mm) from the recording electrode (Figure 1b), and pharmacologically isolated by continuous perfusion of the GABA A antagonist picrotoxin (100 mM).…”

Constitutively Active TRPC3 Channels Regulate Basal Ganglia Output Neurons

“…1 M TTX was used to abolish action potentials. The persistent Na ϩ channel should also be blocked by TTX (Atherton et al, 2005). Under these conditions, the resting membrane potential in SNr GABA neurons was Ϫ50.1 Ϯ 0.8 mV (n ϭ 29).…”

“…After electrophysiologically identifying the SNr GABA neurons (Atherton and Bevan, 2005;Zhou et al, 2006;Lee and Tepper, 2007) (supplemental Fig. 2, available at www.…”

“…Its GABA projection neurons fire high-frequency spontaneous spikes that encode the basal ganglia output (Hikosaka and Wurtz, 1983;Schultz, 1986;Wichmann et al, 1999;Gulley et al, 2002;Sato and Hikosaka, 2002;Maurice et al, 2003;Atherton and Bevan, 2005). The rapid tonic activity of these GABA neurons ensures that their targets such as thalamus and brainstem motor nuclei are under a constant inhibitory control (Deniau et al, 2007;Hikosaka, 2007).…”

“…The persistent, voltagegated, tetrodotoxin (TTX)-sensitive Na ϩ channel is involved, but not sufficient, because the membrane potential is about Ϫ50 mV after blocking the Na ϩ channels with TTX (Atherton and Bevan, 2005;Zhou et al, 2006). This membrane potential is considerably depolarized from the commonly encountered neuronal resting membrane potential of Ϫ60 mV to Ϫ70 mV that is often determined largely by background K ϩ channels and the Na ϩ /K ϩ pump (McCormick, 2004).…”