Review
D1 and D2 dopamine-receptor modulation of striatal glutamatergic signaling in striatal medium spiny neurons

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Dopamine shapes a wide variety of psychomotor functions. This is mainly accomplished by modulating cortical and thalamic glutamatergic signals impinging upon principal medium spiny neurons (MSNs) of the striatum. Several lines of evidence suggest that dopamine D1 receptor signaling enhances dendritic excitability and glutamatergic signaling in striatonigral MSNs, whereas D2 receptor signaling exerts the opposite effect in striatopallidal MSNs. The functional antagonism between these two major striatal dopamine receptors extends to the regulation of synaptic plasticity. Recent studies, using transgenic mice in which cells express D1 and D2 receptors, have uncovered unappreciated differences between MSNs that shape glutamatergic signaling and the influence of DA on synaptic plasticity. These studies have also shown that long-term alterations in dopamine signaling produce profound and cell-type-specific reshaping of corticostriatal connectivity and function.

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.

References (88)

  • W. Schultz

    Behavioral theories and the neurophysiology of reward

    Annu. Rev. Psychol.

    (2006)
  • J.R. Wickens

    Neural mechanisms of reward-related motor learning

    Curr. Opin. Neurobiol.

    (2003)
  • R.L. Albin

    The functional anatomy of basal ganglia disorders

    Trends Neurosci.

    (1989)
  • C.R. Gerfen

    The neostriatal mosaic: multiple levels of compartmental organization in the basal ganglia

    Annu. Rev. Neurosci.

    (1992)
  • D.J. Surmeier

    Coordinated expression of dopamine receptors in neostriatal medium spiny neurons

    J. Neurosci.

    (1996)
  • S.M. Nicola

    Dopaminergic modulation of neuronal excitability in the striatum and nucleus accumbens

    Annu. Rev. Neurosci.

    (2000)
  • D.J. Surmeier

    Microcircuits in the Striatum: Cell Types, Intrinsic Membrane Properties and Neuromodulation

  • G.W. Arbuthnott et al.

    Space, time and dopamine

    Trends Neurosci.

    (2006)
  • H.N. David

    Dopamine-glutamate reciprocal modulation of release and motor responses in the rat caudate-putamen and nucleus accumbens of “intact” animals

    Brain Res. Brain Res. Rev.

    (2005)
  • M. Morari

    Reciprocal dopamine-glutamate modulation of release in the basal ganglia

    Neurochem. Int.

    (1998)
  • D. Herve

    Molecular analysis of the multiple Golf alpha subunit mRNAs in the rat brain

    Brain Res. Mol. Brain Res.

    (1995)
  • P. Svenningsson

    DARPP-32: an integrator of neurotransmission

    Annu. Rev. Pharmacol. Toxicol.

    (2004)
  • G.L. Snyder

    Regulation of phosphorylation of the GluR1 AMPA receptor in the neostriatum by dopamine and psychostimulants in vivo

    J. Neurosci.

    (2000)
  • P.J. Hallett

    Dopamine D1 activation potentiates striatal NMDA receptors by tyrosine phosphorylation-dependent subunit trafficking

    J. Neurosci.

    (2006)
  • S.P. Braithwaite

    Synaptic plasticity: one STEP at a time

    Trends Neurosci.

    (2006)
  • F.J. Lee

    Dual regulation of NMDA receptor functions by direct protein–protein interactions with the dopamine D1 receptor

    Cell

    (2002)
  • L. Scott

    Allosteric changes of the NMDA receptor trap diffusible dopamine 1 receptors in spines

    Proc. Natl. Acad. Sci. USA

    (2006)
  • T. Blank

    The phosphoprotein DARPP-32 mediates cAMP-dependent potentiation of striatal N-methyl-d-aspartate responses

    Proc. Natl. Acad. Sci. USA

    (1997)
  • S.M. Nicola et al.

    Modulation of synaptic transmission by dopamine and norepinephrine in ventral but not dorsal striatum

    J. Neurophysiol.

    (1998)
  • C. Cepeda

    Neuromodulatory actions of dopamine in the neostriatum are dependent upon the excitatory amino acid receptor subtypes activated

    Proc. Natl. Acad. Sci. USA

    (1993)
  • J.C. Liu

    Calcium modulates dopamine potentiation of N-methyl-d-aspartate responses: electrophysiological and imaging evidence

    J. Neurosci. Res.

    (2004)
  • A.G. Carter et al.

    State-dependent calcium signaling in dendritic spines of striatal medium spiny neurons

    Neuron

    (2004)
  • J.N. Kerr et al.

    Action potential timing determines dendritic calcium during striatal up-states

    J. Neurosci.

    (2004)
  • D.J. Surmeier

    Dopamine receptor subtypes colocalize in rat striatonigral neurons

    Proc. Natl. Acad. Sci. USA

    (1992)
  • P. Calabresi

    Intracellular studies on the dopamine-induced firing inhibition of neostriatal neurons in vitro: evidence for D1 receptor involvement

    Neuroscience

    (1987)
  • D.B. Carr

    Transmitter modulation of slow, activity-dependent alterations in sodium channel availability endows neurons with a novel form of cellular plasticity

    Neuron

    (2003)
  • T. Scheuer et al.

    Control of neuronal excitability by phosphorylation and dephosphorylation of sodium channels

    Biochem. Soc. Trans.

    (2006)
  • J.R. Wickens et al.

    Regulation of action-potential firing in spiny neurons of the rat neostriatum in vivo

    J. Neurophysiol.

    (1998)
  • S. Hernandez-Lopez

    D1 receptor activation enhances evoked discharge in neostriatal medium spiny neurons by modulating an L-type Ca2+ conductance

    J. Neurosci.

    (1997)
  • T. Gao

    cAMP-dependent regulation of cardiac L-type Ca2+ channels requires membrane targeting of PKA and phosphorylation of channel subunits

    Neuron

    (1997)
  • D.J. Surmeier

    Modulation of calcium currents by a D1 dopaminergic protein kinase/phosphatase cascade in rat neostriatal neurons

    Neuron

    (1995)
  • P.A. Olson

    G-protein-coupled receptor modulation of striatal CaV1.3 L-type Ca2+ channels is dependent on a Shank-binding domain

    J. Neurosci.

    (2005)
  • M.S. Levine

    Modulatory actions of dopamine on NMDA receptor-mediated responses are reduced in D1A-deficient mutant mice

    J. Neurosci.

    (1996)
  • G.L. Snyder

    A dopamine/D1 receptor/protein kinase A/dopamine- and cAMP-regulated phosphoprotein (Mr 32 kDa)/protein phosphatase-1 pathway regulates dephosphorylation of the NMDA receptor

    J. Neurosci.

    (1998)
  • J. Flores-Hernandez

    Dopamine enhancement of NMDA currents in dissociated medium-sized striatal neurons: role of D1 receptors and DARPP-32

    J. Neurophysiol.

    (2002)
  • R. Vergara

    Spontaneous voltage oscillations in striatal projection neurons in a rat corticostriatal slice

    J. Physiol.

    (2003)
  • K.Y. Tseng et al.

    Dopamine-glutamate interactions controlling prefrontal cortical pyramidal cell excitability involve multiple signaling mechanisms

    J. Neurosci.

    (2004)
  • C. Vilchis

    Ca2+ channels that activate Ca2+-dependent K+ currents in neostriatal neurons

    Neuroscience

    (2000)
  • J.C. Stoof et al.

    Two dopamine receptors: biochemistry, physiology and pharmacology

    Life Sci.

    (1984)
  • S. Hernandez-Lopez

    D2 dopamine receptors in striatal medium spiny neurons reduce L-type Ca2+ currents and excitability via a novel PLCβ1–IP3–calcineurin-signaling cascade

    J. Neurosci.

    (2000)
  • A. Nishi

    Bidirectional regulation of DARPP-32 phosphorylation by dopamine

    J. Neurosci.

    (1997)
  • S.A. Kotecha

    A D2 class dopamine receptor transactivates a receptor tyrosine kinase to inhibit NMDA receptor transmission

    Neuron

    (2002)
  • E. Hernandez-Echeagaray

    Modulation of AMPA currents by D2 dopamine receptors in striatal medium-sized spiny neurons: are dendrites necessary?

    Eur. J. Neurosci.

    (2004)
  • K. Hakansson

    Regulation of phosphorylation of the GluR1 AMPA receptor by dopamine D2 receptors

    J. Neurochem.

    (2006)
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