Modulation of striatal projection systems by dopamine

Abstract

The basal ganglia are a chain of subcortical nuclei that facilitate action selection. Two striatal projection systems--so-called direct and indirect pathways--form the functional backbone of the basal ganglia circuit. Twenty years ago, investigators proposed that the striatum's ability to use dopamine (DA) rise and fall to control action selection was due to the segregation of D(1) and D(2) DA receptors in direct- and indirect-pathway spiny projection neurons. Although this hypothesis sparked a debate, the evidence that has accumulated since then clearly supports this model. Recent advances in the means of marking neural circuits with optical or molecular reporters have revealed a clear-cut dichotomy between these two cell types at the molecular, anatomical, and physiological levels. The contrast provided by these studies has provided new insights into how the striatum responds to fluctuations in DA signaling and how diseases that alter this signaling change striatal function.

Figures

FIGURE 1

Diagram of basal ganglia circuits (a). The striatum receives excitatory corticostriatal and thalamic inputs. Outputs of the basal ganglia arise from the internal segment of the globus pallidus (GPi) and substantia nigra pars reticulata (SNr), which are directed to the thalamus, superior colliculus and pendunculopontine nucleus (PPN). The direct pathway originates from Drd1a expressing SPNs that project to the GPi and SNr output nuclei. The indirect pathway originates from Drd2 expressing SPNs that project only to the external segment of the globus pallidus (GPe), which together with the subthalamic nucleus (STN) contains transynaptic circuits connecting to the basal output nuclei. The direct and indirect pathways provide opponent regulation of the basal ganglia output interface. (b) Fluorescent imaging of a brain section from a mouse expressing EGFP under regulation of the Drd1a promoter shows Drd1a expressing SPNs in the striatum that project axons through the GPe, which terminate in the GPi and GPe. (c) Fluorescent of imaging of a Drd2-EGFP mouse shows that labeled SPNs provide axonal projections that terminate in the GPe, but do not extend to the GPi or SNr.

FIGURE 2

Dichotomous anatomy and physiology of direct and indirect pathway SPNs. Reconstructions of biocytin-filled direct (a) and indirect pathway (b) SPNs from P35–P45 BAC transgenic mice; a GABAergic interneuron (c) is included for comparison. Intrasomatic current injection consistently revealed that indirect pathway SPNs were more excitable (d). Summary of the responses of direct and indirect pathway SPNs to a range of intrasomatic current steps; indirect pathway SPNs were more excitable over a broad range of injected currents. From Gertler et al., 2008.

FIGURE 3

Synaptic plasticity in direct and indirect SPNs. The presynaptic glutamatergic terminal is shown above (orange) and the postsynaptic spine shown below (blue). Black arrowheads depict positive regulation and black circles depict negative regulation. Purple circles in the synaptic cleft represent glutamate. Non-standard abbreviations: CB1R: cannabinoid receptor type 1; AMPAR: α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) receptor; N-methyl-D-aspartic acid (NMDA) receptor; Cav1C: Cav1 containing calcium channel (L-type); PLC: phospholipase C; PKA: protein kinase A; CaMKII: calcium/calmodulin-dependent protein kinase type II; IP3: inositol trisphosphate; D1R: D1 dopamine receptor; D2R: D2 dopamine receptor; EC: endocannabinoid; mGluR5: metabotropic glutamate receptor type 5; LTD: long-term depression; LTP: long-term potentiation. From Surmeier et al., 2009.

FIGURE 4

Thalamic Gating of Glutamatergic Signaling in the Striatum (A) Schematic illustration of cortico- and thalamostriatal glutamatergic projections. Both direct and indirect pathway SPNs receive glutamatergic afferents from the cortex and the thalamus. However, cholinergic interneuron receives glutamatergic inputs primarily from the thalamus. (B) Thalamic inputs efficiently drive cholinergic interneuron and generate a burst-pause firing pattern. By acting at presynaptic M2-class receptors, acetylcholine release transiently suppresses release probability at corticostriatal synapses formed on both direct and indirect pathway SPNs. By acting at postsynaptic M1 receptors, acetylcholine release primarily enhances the responsiveness of D2 SPNs to corticostriatal input for about a second. The pause in cholinergic interneuron activity ensures that there is not a concomitant presynaptic suppression in this window. Thalamic stimulation should activate neighboring cholinergic interneurons as well. The pause is generated in part by recurrent collateral or neighboring interneuron activation of nicotinic receptors on dopaminergic terminals. In this way, the burst of thalamic spikes engages cholinergic interneurons to transiently suppress cortical drive of striatal circuits and then create a second long period in which the striatal network is strongly biased toward cortical activation of D2 SPNs. From Ding et al. (2010).