An Ultra-Short Dopamine Pathway Regulates Basal Ganglia Output

Abstract

Substantia nigra pars reticulata (SNr) is a key basal ganglia output nucleus critical for movement control. Its γ-aminobutyric acid (GABA)-containing projection neurons intermingle with nigral dopamine (DA) neuron dendrites. Here we show that SNr GABA neurons co-express dopamine D1 and D5 receptor mRNAs and also mRNA for TRPC3 channels. Dopamine induced an inward current in these neurons and increased their firing frequency. These effects were mimicked by D1-like agonists, blocked by a D1-like antagonist. D1-like receptor blockade reduced SNr GABA neuron firing frequency and increased their firing irregularity. These D1-like effects were absent in D1 or D5 receptor knockout mice and inhibited by intracellularly applied D1 or D5 receptor antibody. These D1-like effects were also inhibited when the tonically active TRPC3 channels were inhibited by intracellularly applied TRPC3 channel antibody. Furthermore, stimulation of DA neurons induced a direct inward current in SNr GABA neurons that was sensitive to D1-like blockade. Manipulation of DA neuron activity and DA release and inhibition of dopamine reuptake affected SNr GABA neuron activity in a D1-like receptor-dependent manner. Taken together, our findings indicate that dendritically released dopamine tonically excites SNr GABA neurons via D1-D5 receptor co-activation that enhances constitutively active TRPC3 channels, forming an ultra-short SNc→SNr dopamine pathway that regulates the firing intensity and pattern of these basal ganglia output neurons.

Bidirectional plasticity in striatonigral synapses: A switch to balance direct and indirect basal ganglia pathways

“…Although SNr neurons express D 1 class receptors postsynaptically (Zhou et al 2009), cells were voltage clamped at 280 mV and filled with intracellular solutions containing Cs + and QX-314, making it very hard to stimulate modulatable voltage-dependent currents. In addition, plastic changes reported here were accompanied by corresponding changes in the paired-pulse responses and not accompanied by changes in the input resistance of postsynaptic neurons.…”

“…It is known that dopaminergic fibers and neurons innervate SNr (Misgeld 2004;Zhou et al 2009;Rommelfanger and Wichmann 2010) and that they modulate its afferents: striatonigral (direct pathway) (Cameron and Williams 1993;Radnikow and Misgeld 1998;Aceves et al 2011;Chuhma et al 2011) and subthalamonigral (indirect pathway) (Ibañez-Sandoval et al 2006) via presynaptic receptors (Yanovsky et al 2003;Misgeld et al 2007). Accordingly, here we study the dopaminergic modulation of striatonigral synapses and propose its possible role in the selection mechanism.…”

α6β2* and α4β2* Nicotinic Acetylcholine Receptors As Drug Targets for Parkinson's Disease

“…Thus, dendritically released dopamine can influence the activity of dopamine projection neurons themselves via somatodendritic autoreceptors and GABAergic activity within the SN pars reticulata, which forms the output pathway of the direct and indirect circuits ( Fig. 3) (Robertson, 1992;Zhou et al, 2009).…”

Profiling Voltage-gated Potassium Channel mRNA Expression in Nigral Neurons using Single-cell RT-PCR Techniques

“…This is particularly useful when the protein in question can not be detected and localized using other methods such as immunohistochemistry due to low expression level and/or lack of suitable antibody (Surmeier et al 1996;Zhou et al 2009). The high sensitivity and selectivity of scRT-PCR allow the detection of low abundance mRNAs (Surmeier et al 1996).…”

“…The high sensitivity and selectivity of scRT-PCR allow the detection of low abundance mRNAs (Surmeier et al 1996). Additionally, this method allows the correlation of gene expression with electrophysiological and functional properties in individually characterized neurons (Liss et al 2001;Zhou et al 2008Zhou et al , 2009Ding et al 2011). Based on literature evidence and our experience, this method is applicable to every neuron types in the nervous systems.…”