D5 (Not D1) Dopamine Receptors Potentiate Burst-Firing in Neurons of the Subthalamic Nucleus by Modulating an L-Type Calcium Conductance

Abstract

Dopamine is a crucial factor in basal ganglia functioning. In current models of basal ganglia, dopamine is postulated to act on striatal neurons. However, it may also act on the subthalamic nucleus (STN), a key nucleus in the basal ganglia circuit. The data presented here were obtained in brain slices using whole-cell patch clamp. They reveal that D5 dopamine receptors strengthen electrical activity in the subset of subthalamic neurons endowed with burst-firing capacity, resulting in longer discharges of spontaneous or evoked bursts. To distinguish between D1 and D5 subtypes, the action of agonists in the D1/D5 receptor family was first investigated on rat subthalamic neurons. Single-cell reverse transcription-PCR profiling showed that burst-competent neurons only expressed D5 receptors. Accordingly, receptors localized in postsynaptic membranes within the STN were labeled by a D5-specific antibody. Second, agonists in the D1/D5 family were tested in mouse brain slices. It was found that these agonists were active in D1 receptor knock-out mice in a similar way to wild-type mice or rats. This proved that D5 rather than D1 receptors were involved. Pharmacological tools (dihydropyridines, omega-conotoxins, and calciseptine) were used to identify the target of D5 receptors as an L-type channel. This was reached via G-protein and protein kinase A. The action of dopamine on D5 receptors therefore shapes neuronal activity. It contributes to normal information processing in basal ganglia outside striatum. This finding may be useful in drug therapy for various disorders involving changes in STN activity, such as Parkinson's disease and related disorders.

Noradrenergic Modulation of Subthalamic Nucleus Activity: Behavioral and Electrophysiological Evidence in Intact and 6-Hydroxydopamine-Lesioned Rats

“…Experiments were performed as described previously (Baufreton et al, 2003), with the exception that inhibitors of fast synaptic transmission were not used, to enable possible actions of noradrenergic drugs on both neurons and neuronal afferents within STN. Briefly, recordings were made using the blind patch-clamp technique in the wholecell configuration and in current-clamp mode on neurons in 400-mthick midbrain coronal slices, at room temperature.…”

“…Data were recorded and analyzed using pClamp 9.2 software (Molecular Devices, Foster City, CA), Origin 6.1 (Microcal, Northampton, MA), and Prism (GraphPad Software, San Diego, CA). Because plateau potentials and postinhibitory rebound bursts differed from one neuron to another (Baufreton et al, 2003;Hallworth et al, 2003;Wang et al, 2006), each neuron served as both control and test. After a period of 3-5 min used to evaluate access resistance, membrane parameters, pattern of firing at zero current level, and stability of recording, plateau potentials and postinhibitory rebound bursts were activated using four to six incremented current steps.…”

“…A larger proportion of STN neurons are nevertheless burst-competent. Burst-competent neurons give specific responses, called plateau potentials, to short depolarizing current pulses given at hyperpolarized levels (Beurrier et al, 1999;Baufreton et al, 2003;Kass and Mintz, 2006). These responses always outlast the stimuli and resemble evoked bursts.…”

“…These responses always outlast the stimuli and resemble evoked bursts. In addition, burst-competent neurons produce postinhibitory rebound bursts when stimulated by hyperpolarizing steps (Beurrier et al, 1999;Baufreton et al, 2003;Hallworth and Bevan, 2005;Wang et al, 2006). Because burst firing is a hallmark of PD (Bergman et al, 1994), we investigated whether ␣1-and ␣2-AR agonists or antagonists interfered with burst competency.…”

Disruption of orofacial movement topographies in congenic mutants with dopamine D5 but not D4 receptor or DARPP-32 transduction ‘knockout’

“…Alternatively, recent evidence suggests that the presence and physiological role of D 5 receptors in the striatum and related basal ganglia regions may have been underestimated (Rivera et al, 2002b;Baufreton et al, 2003). Though the site(s) mediating these effects remain to be specified, the present data indicate an Cooper, D.C., Onn, S.P., Grace, A.A., Ouimet, C.C., White, F.J., Hyman, S.E., Surmeier, D.J., Girault, J., Nestler, E.J., Greengard, P., 1998.…”