Trends in Neurosciences
ReviewD1 and D2 dopamine-receptor modulation of striatal glutamatergic signaling in striatal medium spiny neurons
Introduction
Dopamine (DA) has long been known to be a crucial modulator of striatal processing of cortical and thalamic signals carried by glutamatergic synapses on the principal neurons of the striatum – medium spiny neurons (MSNs). Regulation of these neurons by DA is important for a wide array of psychomotor functions ascribed to the basal ganglia, such as habit learning and the control of serial movement 1, 2, 3. In spite of its significance, an understanding of the physiological principles underlying MSN regulation has developed slowly. One obstacle has been the lack of homogeneity in the MSN class; there are at least two major subsets of MSN that differ in their expression of DA receptors 4, 5. These subsets cannot be readily identified on the basis of their somatodendritic morphology or electrophysiological properties. Moreover, both cell types are embedded in a rich neuronal network, involving both MSNs and interneurons, that is modulated by DA. This has made it extremely difficult to determine how DA affects MSNs directly and how it affects MSNs indirectly through synaptically coupled neurons. The recent development of mouse lines in which neurons ‘report’ their expression of D1 or D2 receptors by co-expressing enhanced green fluorescent protein (EGFP) promises to accelerate our pace of discovery. Another obstacle is that DA receptors are primarily found in dendrites that are inaccessible to electrodes (the principal tool of electrophysiologists), making direct study of their actions on glutamatergic signaling and dendritic excitability difficult. Optical techniques, such as two photon laser scanning microscopy (2PLSM), are enabling access to these regions, and providing fundamental new insights into their physiology and modulation by DA.
This review largely focuses on what is known about how DA modulates postsynaptic properties that influence glutamatergic synaptic events and their integration by MSNs in the dorsal striatum. Only the actions of the principal DA receptors in this region (D1 and D2 receptors) are discussed. Even with this rather narrow focus, it is impossible to summarize faithfully what has become an enormous literature in the past decade. The reader is referred to several other recent reviews 6, 7, 8. Moreover, there is a rich literature characterizing the impact of glutamate on dopaminergic neurons and DA release that is not covered here 9, 10.
Section snippets
The ‘classical’ model of DA modulation
The most widely circulated model of how DA shapes striatal activity was advanced over 15 years ago by Albin, et al. [3]; they posited that D1 receptors excite MSNs of the ‘direct’ striatonigral pathway and that D2 receptors inhibit MSNs of the ‘indirect’ striatopallidal pathway (Box 1). At the time, the evidence for this model was largely indirect, stemming from estimates of alterations in gene expression, glucose utilization or receptor binding, not direct measures of spiking. Later studies
Modulation of intrinsic excitability and glutamatergic signaling by D1 receptors
Striatonigral MSNs express high levels of D1 receptors 4, 5. These receptors are positively coupled to adenylyl cyclase through Golf [11]. Increases in cytosolic cAMP levels leads to the activation of protein kinase A (PKA) and phosphorylation of various intracellular targets, such as the dual function phosphoprotein DARPP-32 [12], altering cellular function.
A growing number of studies indicate that the D1–PKA cascade has direct effects on the function and trafficking of AMPA receptors and NMDA
Modulation of intrinsic excitability and glutamatergic signaling by D2 receptors
Expression of D2 receptors is high in striatopallidal MSNs. D2 receptors couple to Gi/o proteins, leading to inhibition of adenylyl cyclase through Gαi subunits [39]. In parallel, released Gβγ subunits are capable of reducing Cav2 Ca2+ channel opening and of stimulating phospholipase Cβ isoforms, generating diacylglycerol (DAG) and protein kinase C (PKC) activation as well as inositol (1,4,5)-trisphosphate (IP3) liberation and the mobilization of intracellular Ca2+ stores 40, 41. D2 receptors
The indirect players – striatal interneurons
While considering how DA influences MSN activity, it is impossible to ignore the contribution of interneurons. Most, if not all, of the three types of striatal interneuron express DA receptors [48]. Reviewing this literature is beyond the scope of this article, but a few comments are needed particularly in the context of D2 receptor signaling. The best characterized of the interneurons is the giant, aspiny cholinergic interneuron. In primates, cholinergic interneurons are important determinants
Long-term depression of glutamatergic synaptic transmission
One of the most commonly described functions of DA in the dorsal striatum is to control the induction of plasticity at glutamatergic synapses. Long-term depression (LTD) at corticostriatal synapses has generated the most work. When postsynaptic depolarization is paired with high frequency stimulation (HFS) of glutamatergic fibers, LTD of synaptic transmission is seen in almost all MSNs. Unlike LTD induced by low frequency stimulation in the ventral striatum [55], LTD induction in the dorsal
Long-term potentiation of glutamatergic synaptic transmission
Much less is known about the mechanisms that control induction of long-term potentiation (LTP) than for LTD. Studies in tissue slices have indicated that LTP induced by HFS of corticostriatal glutamatergic inputs (HFS-LTP) depends upon co-activation of D1 and NMDA receptors 69, 70. As noted above, D1 receptor stimulation enhances NMDA receptor currents both directly and indirectly by enhancing L-type Ca2+ channels located nearby 21, 31, although ‘boosting’ by L-type channels appears not to be
The role of dendritic ion channels in the induction and expression of synaptic plasticity
How does dendritic excitability – and dopaminergic modulation of this excitability – affect the induction and expression of plasticity at glutamatergic synapses? The majority of the studies that have shaped thinking in the field have relied upon recordings from neurons filled with K+ and Na+ channel blockers (Cs+ and QX-314), effectively removing postsynaptic excitability from the plasticity equation. This has been a valuable, simplifying manipulation but it does not mimic the situation in vivo
Concluding remarks
Although we are still some way from a secure grasp of how DA affects the activity of striatal circuits, there are some tentative conclusions that can be drawn. Acting principally through D2 receptors, DA reduces glutamate release as well as the postsynaptic responsiveness of striatopallidal MSNs to released glutamate. This short-term modulation is complemented by D2-receptor-dependent promotion of long-term depression of glutamatergic synaptic transmission. Our grasp of how DA modulates
Acknowledgments
This work was supported by grants from NIH (NS 34696) and the Picower Foundation.
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