Skip to main content
PMC home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2012 Apr 1.
Published in final edited form as: Curr Opin Neurobiol. 2011 Feb 16;21(2):322–327. doi: 10.1016/j.conb.2011.01.005

Neuromodulatory Control of Striatal Plasticity and Behavior

Talia N Lerner 1,3, Anatol C Kreitzer 1,2,3
PMCID: PMC3092792  NIHMSID: NIHMS276456  PMID: 21333525

Abstract

Excitatory synapses onto projection neurons in the striatum, the input nucleus of the basal ganglia, play a key role in regulating basal ganglia circuit function and are a major site of long-term synaptic plasticity. Here, we review the mechanisms and regulation of both long-term potentiation and long-term depression at these synapses. In particular, we highlight the role that neuromodulators play in determining the strength and direction of plasticity, which ultimately shapes the balance of activity in basal ganglia circuits and regulates motor behavior.

Introduction

The basal ganglia are a network of subcortical brain nuclei important for action selection and motor learning [1–4]. Our understanding of basal ganglia circuit function has long been dominated by the classic Albin-DeLong model, based on the clinical manifestations of Parkinson’s and Huntington’s Diseases. In this model, information flows through the basal ganglia in two parallel circuits – the direct and the indirect pathways – which diverge from the main input nucleus of the basal ganglia, the striatum, and converge again in the output nuclei of the basal ganglia. The Albin-DeLong model postulates that increased activity of the direct pathway facilitates movement, whereas increased activity of the indirect pathway inhibits movement. While this is an oversimplification of the complex basal ganglia circuit (for review see [5]), recent tests of the model have lent support to its general structure. Using viral-mediated cell-type-specific expression of channelrhodopsin-2, our lab demonstrated that firing rates of direct- and indirect-pathway medium spiny neurons (MSNs), the projection neurons of the striatum, control different aspects of movement in the directions predicted by the Albin-DeLong model [6]. Further evidence for this hypothesis comes from experiments that selectively lesioned indirect-pathway MSNs, a manipulation that led to dramatic increases in locomotor behavior [7].

Given that the firing rates of direct- and indirect-pathway MSNs directly influence movement, it is important to ask what physiological mechanisms regulate MSN firing rates. In order to fire any spikes at all, MSNs rely on excitatory input from cortex and thalamus [8]. Therefore, modulation of excitatory synaptic input strength should be particularly effective at modulating MSN firing rates. Indeed, plasticity at excitatory synapses onto MSNs is involved in motor skill acquisition [9,10], and is disrupted in animal models of movement disorders, including Parkinson’s disease and dystonia [11–16].

Although synaptic plasticity at excitatory inputs to MSNs has been studied extensively, the detailed mechanisms underlying its expression and regulation remain unknown. Fortunately, our understanding of plasticity in the striatum has benefitted greatly from the recent generation and use of BAC transgenic lines that allow easy identification of MSNs of the direct and indirect pathways [17,18]. The BAC reporter lines rely on the differential expression of G-protein-coupled receptors (GPCRs) in the two types of MSNs: indirect-pathway neurons selectively express Gi-coupled dopamine D2 and Gs-coupled adenosine A2A receptors, whereas direct-pathway neurons selectively express Gi-coupled muscarinic acetylcholine M4 receptors and Gs-coupled dopamine D1 receptors. Thus, fluorescent proteins expressed from the promoters of these receptors selectively label either the indirect or the direct pathway. Differential expression of these Gi and Gs-coupled GPCRs by the two MSN subtypes is not just an experimentally useful coincidence, but reflects important differences in the way that the neuromodulators dopamine, adenosine, and acetylcholine control plasticity in the two pathways. Understanding the molecular mechanisms that regulate LTP and LTD in the striatum is critical because it will allow us to better understand the circuit-level mechanisms that underlie action selection and motor learning by the basal ganglia circuit. Furthermore, understanding the mechanisms by which dopamine, adenosine, and acetylcholine control striatal plasticity and basal ganglia circuit function will aid the search for new treatments for Parkinson’s disease and other basal ganglia disorders.

Indirect-Pathway LTD

In indirect-pathway MSNs, long-term depression (LTD) of excitatory inputs occurs in response to high frequency (100Hz) stimulation paired with postsynaptic depolarization, or in response to negative spike timing (i.e. synaptic stimulation delivered shortly after the MSN spikes) [11,12,19–21]. The mechanisms underlying indirect-pathway LTD appear to be similar using both protocols. LTD is induced postsynaptically by activation of Gq-coupled mGluRs and L-type calcium channels, which together lead to the mobilization of endocannabinoids [11,12,22–24]. Endocannabinoids then travel retrogradely across the synaptic cleft and activate presynaptic CB1 receptors [22,25]. Prolonged activation of CB1 receptors (several minutes) leads to presynaptic expression of LTD as a decrease in release probability [26]. Successful induction of indirect-pathway LTD requires activation of dopamine D2 receptors, but also lack of activation of postsynaptic adenosine A2A receptors [12,27]. Thus, by regulating the activation of these GPCRs, dopamine and adenosine gate LTD induction in indirect-pathway MSNs.

The most likely downstream mediator of D2 and A2A receptor signaling is cAMP. D2 and A2A receptors are oppositely coupled to cAMP accumulation, just as they are to LTD induction. Additionally, adenylyl cyclase 5 knockout mice have impaired indirect-pathway LTD and the mechanism of LTD impairment is upstream of Gq-coupled mGluRs [28]. We do not, however, understand the mechanism of D2 and A2A receptor modulation of LTD downstream of cAMP. Is PKA involved? If so, what are its relevant substrates? Mapping out the convergent signaling cascades of D2, A2A, and mGlu receptors as well as L-type calcium channels remains an important area of research.

Indirect-Pathway LTP

Long-term potentiation (LTP) was first observed at excitatory synapses onto MSNs using sharp electrodes and an extracellular solution containing 0 mM Mg2+ [29]. Under these conditions, LTP is induced by high-frequency stimulation. More recently, LTP has been elicited in the presence of physiological Mg2+ concentrations using perforated patch recordings and positive spike timing (i.e. synaptic stimulation delivered shortly before the MSN is induced to spike) [12,30]. LTP is postsynaptically expressed and depends on postsynaptic NMDA receptor activation [10,12,29,31]. Two recent studies also indicate that the neurotrophic factors FGF and BDNF promote LTP in MSNs, likely through enhancement of NMDA currents [31,32].

In indirect-pathway MSNs specifically, LTP requires A2A receptor activation as well as a lack of activation of D2 receptors, since a D2 agonist can convert the spike-timing dependent LTP into LTD [12,31]. Thus, D2 and A2A receptors gate LTP induction as well as LTD induction. High dopamine levels and low adenosine levels will shift plasticity induction in indirect-pathway MSNs towards LTD. In contrast, low dopamine levels and high adenosine levels will promote LTP in indirect-pathway MSNs.

As with LTD, it is not known how D2 and A2A receptors are able to modulate LTP. However, some clues exist. Since sharp electrodes or perforated patch recordings are required to observe LTP, diffusible signaling molecules are likely involved. Additionally, it was recently shown that D2 and A2A receptors oppositely modulate NMDA receptor signaling through PKA [33]. It is not yet clear, however, whether postsynaptic PKA is in fact involved in LTP and, if so, what the relevant substrates of PKA are for this process.

Direct-Pathway LTD

LTD in direct-pathway MSNs is not as well studied as it is in indirect-pathway MSNs, but the literature suggests that its mechanisms, involving postsynaptic Gq-coupled mGluRs and L-type calcium channels and presynaptic CB1 receptors, are similar. LTD in direct-pathway MSNs is blocked by a CB1 receptor antagonist as well as by a Gq-coupled mGluR antagonist [12]. Additionally, LTD induced by pharmacological activation of L-type calcium channels has been observed in both direct- and indirect-pathway MSNs [24].

Although the mechanisms of LTD at excitatory synapses onto direct-pathway MSNs are probably similar to those in indirect-pathway MSNs, the activation of mGluRs and L-type calcium channel signaling, and therefore LTD itself, may be gated by different neuromodulator receptors. Direct-pathway MSNs do not express D2 and A2A receptors, but they do express a complementary pair of Gs- and Gi-coupled receptors: dopamine D1 and acetylcholine M4 receptors [34]. Using a spike-timing dependent induction protocol, Shen et al. observed LTD in direct-pathway MSNs when D1 receptors were blocked [12]. This finding may explain why earlier studies of striatal LTD [11] failed to observe LTD at direct-pathway synapses: if dopamine release is stimulated by an intrastriatal stimulating electrode, this dopamine can activate D1 receptors and block direct-pathway LTD. D1 receptors may thus act similarly to A2A receptors in the indirect pathway, whereas M4 receptors could act similarly to D2 receptors in the indirect pathway. The role of M4 receptors in LTD has not yet been explored experimentally, but M4 is an attractive candidate for a Gi-coupled D2-analog in the direct pathway [35].

Direct-Pathway LTP

The only existing study of LTP in identified direct-pathway MSNs to date showed that LTP can be induced at direct-pathway synapses by positive spike timing using perforated-patch whole-cell recordings [12]. This LTP required NMDA receptors, just as it did in indirect-pathway MSNs, but also depended on activation of D1 receptors. An older study using sharp electrodes also found that D1 receptors are required for LTP [36]. Thus, in LTP as in LTD, D1 receptors appear to act analogously to A2A receptors in the indirect pathway, implying that cAMP/PKA signaling is likely required to initiate LTP induction in direct-pathway MSNs.

Striatal neuromodulators transduce behavioral states into appropriate patterns of motor behavior

An important theme that emerges from the body of data summarized above is that the relative levels of neuromodulators present in the striatum at any given time determines whether excitatory glutamatergic signaling causes synapses in the striatum to increase or decrease in strength. Indeed, the behavioral state of an animal can influence the direction of striatal plasticity observed [37]. This suggests that one important role of striatal neuromodulators is to transduce salient environmental cues or changes in internal state into appropriate patterns of motor behavior (Figure 1). Release of the most widely studied striatal neuromodulator, dopamine, occurs in response to a variety of stimuli on a wide range of timescales (from milliseconds to hours) [38]. While reward-related signals are generally fast, slower modulation of striatal dopamine occurs in response to internal states such as uncertainty, curiosity, hunger, aggression and fatigue [38].

Figure 1. Regulation of synaptic plasticity and behavioral state by striatal neuromodulators.

Figure 1

Open in a new tab

Left, when the levels of dopamine are high relative to adenosine and acetylcholine, cAMP/PKA activity is low in indirect-pathway MSNs, biasing excitatory synapses onto those cells towards LTD. Meanwhile, cAMP/PKA activity is high in direct-pathway MSNs, biasing excitatory synapses onto those cells towards LTP. Indirect-pathway LTD and direct pathway LTP are proposed to cause an active, motivated behavioral state. Right, when the levels of dopamine are low relative to adenosine and acetylcholine, cAMP/PKA activity is high in indirect-pathway MSNs, biasing excitatory synapses onto those cells towards LTP. Meanwhile, cAMP/PKA activity is low in direct-pathway MSNs, biasing excitatory synapses onto those cells towards LTD. Indirect-pathway LTP and direct pathway LTD are proposed to induce an inactive, apathetic behavioral state.

Hunger, an extremely ethologically relevant internal state, increases dopamine levels [39,40]. High dopamine levels will cause a weakening of indirect-pathway synapses and strengthening of direct-pathway synapses, leading to increased locomotor behavior required to forage for food. In contrast, a sated animal would have lower dopamine levels that would cause LTP of indirect-pathway synapses and LTD of direct-pathway synapses, leading to more immobility, enabling the animal to digest food and store energy.

As another example, consider the role of adenosine in the CNS. It is hypothesized to provide a readout of overall metabolic load (though its exact mechanisms of release in the striatum are unclear) [41]. Increased levels of adenosine, perhaps associated with prolonged wakefulness, would lead to activation of striatal A2A receptors on indirect-pathway MSNs. This in turn would promote LTP and inhibit LTD at excitatory afferent synapses, leading to an overall increase in indirect-pathway MSN activity and a reduction in locomotor activity, enabling the animal to sleep or conserve energy.

In healthy animals, variations in the levels of striatal neuromodulators will lead to motivated or apathetic states within the normal range of the animal’s behavior. However, persistently high striatal dopamine may cause hyperactivity and dyskinesias whereas persistently low dopamine, as in Parkinson’s disease, causes immobility. An important assumption of this scheme is that “long-term” plasticity in the striatum may only last for minutes to hours, or until it is reversed by an opposing form of synaptic plasticity (an issue that is discussed in the next section of this review). This is in contrast to long-term plasticity in motor cortex, which is associated with motor memories that can last for the lifetime of the organism [42,43]. In fact, motor memory may be initially shaped by the basal ganglia but ultimately consolidated in motor cortex.

LTD and LTP: Opponent processes?

Functionally, LTD and LTP are opponent processes, but are the induction of LTD and the induction of LTP linked mechanistically? An attractive hypothesis that emerges from the body of data summarized above is that cAMP/PKA signaling links the two processes by oppositely modulating them. Enhanced PKA activity increases NMDA receptor signaling and therefore should promote LTP. Low PKA activity (or at least low cAMP) biases MSNs towards LTD. Testing of this hypothesis awaits future experiments. In the meantime, however, it also begs the question: what are the targets of PKA at excitatory synapses onto MSNs? How could PKA influence both Gq-coupled mGluR and L-type calcium channel signaling (for LTD) and NMDA receptor signaling (for LTP)?

There are many possible targets for PKA. For LTP, one possibility is that PKA phosphorylates NMDA receptors directly to activate them. Other possible targets include the striatal-enriched phosphatases STEP46 and STEP61, and DARPP-32, all of which are expressed by MSNs and contain known PKA phosphorylation sites [44,45]. PKA phosphorylation causes DARPP-32 to inhibit PP1. Inhibition of PP1, in turn, increases the phosphorylation of NMDA and AMPA receptors, activating them [46]. PKA phosphorylation, as well as inhibition of PP1, also regulates STEP activity. Postsynaptic STEP and DARPP-32 signaling might be especially important for LTP since LTP is postsynaptically expressed. In agreement with this view, a mutant substrate-trapping form of STEP prevents LTP but not LTD [47] and the loss of DARPP-32 prevents LTP in both direct- and indirect-pathway MSNs [48].

For LTD, the possible targets of PKA (postsynaptically) must be involved in the mGluR or L-type calcium channel signaling pathways that lead to endocannabinoid production. One group found that D1 receptor agonists potentiated Gq signaling in a PKA-dependent manner in HEK cells [49]. PKA might be able to regulate Gq signaling by phosphorylating it directly, or by phosphorylating some downstream components of the signaling pathway such as PLCβ or IP3 receptors, or by phosphorylating Regulators of G-protein Signaling (RGSs) or G-protein-coupled Receptor Kinases (GRKs). Others have found that D1 receptor agonists can enhance L-type calcium channel currents via cAMP/PKA signaling [50,51], raising the possibility that L-type calcium channels could be a direct or indirect target of PKA modulation.

The issue of whether LTD and LTP are mechanistically linked also raises another critical unanswered question in the field. How can LTD and LTP act as opponent processes if the former is expressed presynaptically while the latter is expressed postsynaptically? By undergoing LTD, and then later LTP, a MSN synapse would not return to its original state, but would end up with a low presynaptic release probability but a robust ability to detect and respond to release events postsynaptically. Do all MSN excitatory synapses eventually become “locked” in this state? If so, synaptogenesis would be required to support continued plasticity (and, presumably, motor learning) in adulthood and the hypothesis put forth in the previous section would be invalid. Alternatively, there might be homeostatic resetting mechanisms for MSN synapse strength. Such resetting mechanisms might be active – de-potentiation/de-depression mechanisms – or passive – slow resetting caused by constant cycling of cellular components. De-potentiation of MSN synapses has been observed using low-frequency stimulation (1–2 Hz) and involves apparently postsynaptic mechanisms including signaling by DARPP-32, PP1 and STEP [31,47,52,53]. De-depression of endocannabinoid-mediated LTD has not, to our knowledge, been demonstrated. Evidence for passive resetting of MSN synapse strength is also scant, but passive resetting cannot yet be excluded as a possibility. The solution to the question of how MSNs maintain their ability to undergo plasticity will be critical to our understanding of how the basal ganglia support action selection and learning processes.

Conclusion

Our understanding of striatal plasticity has advanced rapidly in the last few years. With the advent of BAC transgenic mice that allow identification of direct- and indirect-pathway MSNs both in vitro and in vivo, the field has finally begun to come into focus. Recordings from different populations of striatal MSNs have demonstrated distinct forms of synaptic plasticity at their excitatory inputs, which are differentially regulated by neuromodulators. These striatal neuromodulators may represent a key interface between the state of an animal and its motor behavior, enabling an animal to adjust its activity patterns in accordance with an ever changing internal and external environment.

Footnotes

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

References

  • 1.Graybiel AM, Aosaki T, Flaherty AW, Kimura M. The basal ganglia and adaptive motor control. Science. 1994;265:1826–1831. doi: 10.1126/science.8091209. [DOI] [PubMed] [Google Scholar]
  • 2.Yin HH, Knowlton BJ. The role of the basal ganglia in habit formation. Nat Rev Neurosci. 2006;7:464–476. doi: 10.1038/nrn1919. [DOI] [PubMed] [Google Scholar]
  • 3.Packard MG, Knowlton BJ. Learning and memory functions of the Basal Ganglia. Annu Rev Neurosci. 2002;25:563–593. doi: 10.1146/annurev.neuro.25.112701.142937. [DOI] [PubMed] [Google Scholar]
  • 4.Hikosaka O, Takikawa Y, Kawagoe R. Role of the basal ganglia in the control of purposive saccadic eye movements. Physiol Rev. 2000;80:953–978. doi: 10.1152/physrev.2000.80.3.953. [DOI] [PubMed] [Google Scholar]
  • 5.DeLong M, Wichmann T. Update on models of basal ganglia function and dysfunction. Parkinsonism Relat Disord. 2009;15 Suppl 3:S237–S240. doi: 10.1016/S1353-8020(09)70822-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Kravitz AV, Freeze BS, Parker PRL, Kay K, Thwin MT, Deisseroth K, Kreitzer AC. Regulation of parkinsonian motor behaviours by optogenetic control of basal ganglia circuitry. Nature. 2010;466:622–626. doi: 10.1038/nature09159. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Durieux PF, Bearzatto B, Guiducci S, Buch T, Waisman A, Zoli M, Schiffmann SN, de Kerchove d'Exaerde A. D2R striatopallidal neurons inhibit both locomotor and drug reward processes. Nat Neurosci. 2009;12:393–395. doi: 10.1038/nn.2286. [DOI] [PubMed] [Google Scholar]
  • 8.Wilson CJ, Kawaguchi Y. The origins of two-state spontaneous membrane potential fluctuations of neostriatal spiny neurons. J Neurosci. 1996;16:2397–2410. doi: 10.1523/JNEUROSCI.16-07-02397.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Yin HH, Mulcare SP, Hilario MR, Clouse E, Holloway T, Davis MI, Hansson AC, Lovinger DM, Costa RM. Dynamic reorganization of striatal circuits during the acquisition and consolidation of a skill. Nat Neurosci. 2009;12:333–341. doi: 10.1038/nn.2261. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Dang MT, Yokoi F, Yin HH, Lovinger DM, Wang Y, Li Y. Disrupted motor learning and long-term synaptic plasticity in mice lacking NMDAR1 in the striatum. Proc Natl Acad Sci U S A. 2006;103:15254–15259. doi: 10.1073/pnas.0601758103. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11. Kreitzer AC, Malenka RC. Endocannabinoid-mediated rescue of striatal LTD and motor deficits in Parkinson's disease models. Nature. 2007;445:643–647. doi: 10.1038/nature05506. This study was among the first to show that endocannabinoid-dependent LTD in the direct and indirect pathways is differentially regulated. D2 receptor activation allows LTD to take place in indirect-pathway MSNs in response to high-frequency stimulation by potentiating mGluR-induced endocannabinoid production.
  • 12. Shen W, Flajolet M, Greengard P, Surmeier DJ. Dichotomous dopaminergic control of striatal synaptic plasticity. Science. 2008;321:848–851. doi: 10.1126/science.1160575. This was the first study to examine bidirectional plasticity in pathway-identified MSNs. It demonstrated that both LTD and LTP can occur in the direct and the indirect pathways using spike-timing dependent plasticity protocols, but that plasticity in the two pathways is differentially regulated by D1, D2, and A2A receptors.
  • 13.Kitada T, Pisani A, Karouani M, Haburcak M, Martella G, Tscherter A, Platania P, Wu B, Pothos EN, Shen J. Impaired dopamine release and synaptic plasticity in the striatum of parkin−/− mice. J Neurochem. 2009;110:613–621. doi: 10.1111/j.1471-4159.2009.06152.x. [DOI] [PubMed] [Google Scholar]
  • 14.Kitada T, Pisani A, Porter DR, Yamaguchi H, Tscherter A, Martella G, Bonsi P, Zhang C, Pothos EN, Shen J. Impaired dopamine release and synaptic plasticity in the striatum of PINK1-deficient mice. Proc Natl Acad Sci U S A. 2007;104:11441–11446. doi: 10.1073/pnas.0702717104. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Kurz A, Double KL, Lastres-Becker I, Tozzi A, Tantucci M, Bockhart V, Bonin M, Garcia-Arencibia M, Nuber S, Schlaudraff F, et al. A53T-alpha-synuclein overexpression impairs dopamine signaling and striatal synaptic plasticity in old mice. PLoS One. 5:e11464. doi: 10.1371/journal.pone.0011464. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Peterson DA, Sejnowski TJ, Poizner H. Convergent evidence for abnormal striatal synaptic plasticity in dystonia. Neurobiol Dis. 37:558–573. doi: 10.1016/j.nbd.2009.12.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Shuen JA, Chen M, Gloss B, Calakos N. Drd1a-tdTomato BAC transgenic mice for simultaneous visualization of medium spiny neurons in the direct and indirect pathways of the basal ganglia. J Neurosci. 2008;28:2681–2685. doi: 10.1523/JNEUROSCI.5492-07.2008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Gong S, Zheng C, Doughty ML, Losos K, Didkovsky N, Schambra UB, Nowak NJ, Joyner A, Leblanc G, Hatten ME, et al. A gene expression atlas of the central nervous system based on bacterial artificial chromosomes. Nature. 2003;425:917–925. doi: 10.1038/nature02033. [DOI] [PubMed] [Google Scholar]
  • 19.Calabresi P, Maj R, Pisani A, Mercuri NB, Bernardi G. Long-term synaptic depression in the striatum: physiological and pharmacological characterization. J Neurosci. 1992;12:4224–4233. doi: 10.1523/JNEUROSCI.12-11-04224.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Fino E, Glowinski J, Venance L. Bidirectional activity-dependent plasticity at corticostriatal synapses. J Neurosci. 2005;25:11279–11287. doi: 10.1523/JNEUROSCI.4476-05.2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Ade KK, Lovinger DM. Anandamide regulates postnatal development of long-term synaptic plasticity in the rat dorsolateral striatum. J Neurosci. 2007;27:2403–2409. doi: 10.1523/JNEUROSCI.2916-06.2007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Sung KW, Choi S, Lovinger DM. Activation of group I mGluRs is necessary for induction of long-term depression at striatal synapses. J Neurophysiol. 2001;86:2405–2412. doi: 10.1152/jn.2001.86.5.2405. [DOI] [PubMed] [Google Scholar]
  • 23.Kreitzer AC, Malenka RC. Dopamine modulation of state-dependent endocannabinoid release and long-term depression in the striatum. J Neurosci. 2005;25:10537–10545. doi: 10.1523/JNEUROSCI.2959-05.2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Adermark L, Lovinger DM. Combined activation of L-type Ca2+ channels and synaptic transmission is sufficient to induce striatal long-term depression. J Neurosci. 2007;27:6781–6787. doi: 10.1523/JNEUROSCI.0280-07.2007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Gerdeman GL, Ronesi J, Lovinger DM. Postsynaptic endocannabinoid release is critical to long-term depression in the striatum. Nat Neurosci. 2002;5:446–451. doi: 10.1038/nn832. [DOI] [PubMed] [Google Scholar]
  • 26.Choi S, Lovinger DM. Decreased probability of neurotransmitter release underlies striatal long-term depression and postnatal development of corticostriatal synapses. Proc Natl Acad Sci U S A. 1997;94:2665–2670. doi: 10.1073/pnas.94.6.2665. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27. Lerner TN, Horne EA, Stella N, Kreitzer AC. Endocannabinoid signaling mediates psychomotor activation by adenosine A2A antagonists. J Neurosci. 2010;30:2160–2164. doi: 10.1523/JNEUROSCI.5844-09.2010. This study finds that blocking A2A receptors allows LTD to occur in indirect-pathway MSNs in response to a stimulus that would not otherwise be sufficient for LTD. The ability of A2A antagonists to promote LTD in the indirect pathway may underlie the increases in motor activity observed after administering A2A antagonists in vivo.
  • 28. Kheirbek MA, Britt JP, Beeler JA, Ishikawa Y, McGehee DS, Zhuang X. Adenylyl cyclase type 5 contributes to corticostriatal plasticity and striatum-dependent learning. J Neurosci. 2009;29:12115–12124. doi: 10.1523/JNEUROSCI.3343-09.2009. The authors of this study generated mice lacking a striatal-enriched isoform of adenylyl cyclase, AC5. The AC5 knockout mice had impaired LTD. The mechanism of this impairment was upstream of Gq-coupled mGluRs, but downstream of D2 receptors. This finding provides evidence that adenylyl cyclase mediates the effects of D2 receptors on LTD, probably by modulating some aspect of mGluR signaling.
  • 29.Calabresi P, Pisani A, Mercuri NB, Bernardi G. Long-term Potentiation in the Striatum is Unmasked by Removing the Voltage-dependent Magnesium Block of NMDA Receptor Channels. Eur J Neurosci. 1992;4:929–935. doi: 10.1111/j.1460-9568.1992.tb00119.x. [DOI] [PubMed] [Google Scholar]
  • 30.Fino E, Paille V, Cui Y, Morera-Herreras T, Deniau JM, Venance L. Distinct coincidence detectors govern the corticostriatal spike timing-dependent plasticity. J Physiol. 588:3045–3062. doi: 10.1113/jphysiol.2010.188466. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Flajolet M, Wang Z, Futter M, Shen W, Nuangchamnong N, Bendor J, Wallach I, Nairn AC, Surmeier DJ, Greengard P. FGF acts as a co-transmitter through adenosine A(2A) receptor to regulate synaptic plasticity. Nat Neurosci. 2008;11:1402–1409. doi: 10.1038/nn.2216. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Jia Y, Gall CM, Lynch G. Presynaptic BDNF promotes postsynaptic long-term potentiation in the dorsal striatum. J Neurosci. 30:14440–14445. doi: 10.1523/JNEUROSCI.3310-10.2010. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33. Higley MJ, Sabatini BL. Competitive regulation of synaptic Ca2+ influx by D2 dopamine and A2A adenosine receptors. Nat Neurosci. 13:958–966. doi: 10.1038/nn.2592. The authors demonstrate, using 2-photon glutamate uncaging and 2-photon imaging of spine calcium, that D2 and A2A receptors modulate NMDA receptor-dependent spine calcium influx via PKA signaling in indirect-pathway MSNs. Since PKA mediates the effects of D2 and A2A receptors on NMDA receptors, it is likely to be involved in striatal LTP, which is NMDA receptor-dependent.
  • 34.Kreitzer AC, Malenka RC. Striatal plasticity and basal ganglia circuit function. Neuron. 2008;60:543–554. doi: 10.1016/j.neuron.2008.11.005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Jeon J, Dencker D, Wortwein G, Woldbye DP, Cui Y, Davis AA, Levey AI, Schutz G, Sager TN, Mork A, et al. A subpopulation of neuronal M4 muscarinic acetylcholine receptors plays a critical role in modulating dopamine-dependent behaviors. J Neurosci. 30:2396–2405. doi: 10.1523/JNEUROSCI.3843-09.2010. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Kerr JN, Wickens JR. Dopamine D-1/D-5 receptor activation is required for long-term potentiation in the rat neostriatum in vitro. J Neurophysiol. 2001;85:117–124. doi: 10.1152/jn.2001.85.1.117. [DOI] [PubMed] [Google Scholar]
  • 37.Stoetzner CR, Pettibone JR, Berke JD. State-dependent plasticity of the corticostriatal pathway. Neuroscience. 165:1013–1018. doi: 10.1016/j.neuroscience.2009.11.031. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Schultz W. Multiple dopamine functions at different time courses. Annu Rev Neurosci. 2007;30:259–288. doi: 10.1146/annurev.neuro.28.061604.135722. [DOI] [PubMed] [Google Scholar]
  • 39.Narayanan NS, Guarnieri DJ, DiLeone RJ. Metabolic hormones, dopamine circuits, and feeding. Front Neuroendocrinol. 31:104–112. doi: 10.1016/j.yfrne.2009.10.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Bonci A, Borgland S. Role of orexin/hypocretin and CRF in the formation of drug-dependent synaptic plasticity in the mesolimbic system. Neuropharmacology. 2009;56 Suppl 1:107–111. doi: 10.1016/j.neuropharm.2008.07.024. [DOI] [PubMed] [Google Scholar]
  • 41.Dunwiddie TV, Masino SA. The role and regulation of adenosine in the central nervous system. Annu Rev Neurosci. 2001;24:31–55. doi: 10.1146/annurev.neuro.24.1.31. [DOI] [PubMed] [Google Scholar]
  • 42.Yang G, Pan F, Gan WB. Stably maintained dendritic spines are associated with lifelong memories. Nature. 2009;462:920–924. doi: 10.1038/nature08577. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43.Xu T, Yu X, Perlik AJ, Tobin WF, Zweig JA, Tennant K, Jones T, Zuo Y. Rapid formation and selective stabilization of synapses for enduring motor memories. Nature. 2009;462:915–919. doi: 10.1038/nature08389. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44.Paul S, Snyder GL, Yokakura H, Picciotto MR, Nairn AC, Lombroso PJ. The Dopamine/D1 receptor mediates the phosphorylation and inactivation of the protein tyrosine phosphatase STEP via a PKA-dependent pathway. J Neurosci. 2000;20:5630–5638. doi: 10.1523/JNEUROSCI.20-15-05630.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45.Kuroiwa M, Bateup HS, Shuto T, Higashi H, Tanaka M, Nishi A. Regulation of DARPP-32 phosphorylation by three distinct dopamine D1-like receptor signaling pathways in the neostriatum. J Neurochem. 2008;107:1014–1026. doi: 10.1111/j.1471-4159.2008.05702.x. [DOI] [PubMed] [Google Scholar]
  • 46.Greengard P, Allen PB, Nairn AC. Beyond the dopamine receptor: the DARPP-32/protein phosphatase-1 cascade. Neuron. 1999;23:435–447. doi: 10.1016/s0896-6273(00)80798-9. [DOI] [PubMed] [Google Scholar]
  • 47. Tashev R, Moura PJ, Venkitaramani DV, Prosperetti C, Centonze D, Paul S, Lombroso PJ. A substrate trapping mutant form of striatal-enriched protein tyrosine phosphatase prevents amphetamine-induced stereotypies and long-term potentiation in the striatum. Biol Psychiatry. 2009;65:637–645. doi: 10.1016/j.biopsych.2008.10.008. The authors of this study generated a dominant negative mutant form of striatal-enriched protein (STEP) and used it to examine the role of STEP in striatal plasticity. The mutant STEP blocked striatal LTP induced by high-frequency stimulation in 0 Mg2+. Interestingly, the mutant STEP also allowed robust depotentiation of striatal synapses induced by low-frequency stimulation. The mutant STEP did not, however, block striatal LTD induced by high-frequency stimulation in physiological Mg2+, consistent with the idea that separate mechanisms downstream of PKA regulate LTP and LTD.
  • 48. Bateup HS, Santini E, Shen W, Birnbaum S, Valjent E, Surmeier DJ, Fisone G, Nestler EJ, Greengard P. Distinct subclasses of medium spiny neurons differentially regulate striatal motor behaviors. Proc Natl Acad Sci U S A. 107:14845–14850. doi: 10.1073/pnas.1009874107. The authors generate mice lacking DARPP-32 specifically in direct- or indirect-pathway MSNs. They find that DARPP-32 knockout prevents LTP in both MSN subtypes, providing evidence that DARPP-32 is a downstream effector of PKA signaling during striatal LTP. The loss of LTP in the direct pathway due to DARPP-32 knockout decreases locomotion, whereas the same manipulation in the indirect pathway increases locomotion.
  • 49.Dai R, Ali MK, Lezcano N, Bergson C. A crucial role for cAMP and protein kinase A in D1 dopamine receptor regulated intracellular calcium transients. Neurosignals. 2008;16:112–113. doi: 10.1159/000111557. [DOI] [PubMed] [Google Scholar]
  • 50.Surmeier DJ, Bargas J, Hemmings HC, Jr, Nairn AC, Greengard P. Modulation of calcium currents by a D1 dopaminergic protein kinase/phosphatase cascade in rat neostriatal neurons. Neuron. 1995;14:385–397. doi: 10.1016/0896-6273(95)90294-5. [DOI] [PubMed] [Google Scholar]
  • 51.Hernandez-Lopez S, Bargas J, Surmeier DJ, Reyes A, Galarraga E. D1 receptor activation enhances evoked discharge in neostriatal medium spiny neurons by modulating an L-type Ca2+ conductance. J Neurosci. 1997;17:3334–3342. doi: 10.1523/JNEUROSCI.17-09-03334.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 52.Picconi B, Centonze D, Hakansson K, Bernardi G, Greengard P, Fisone G, Cenci MA, Calabresi P. Loss of bidirectional striatal synaptic plasticity in L-DOPA-induced dyskinesia. Nat Neurosci. 2003;6:501–506. doi: 10.1038/nn1040. [DOI] [PubMed] [Google Scholar]
  • 53.Centonze D, Costa C, Rossi S, Prosperetti C, Pisani A, Usiello A, Bernardi G, Mercuri NB, Calabresi P. Chronic cocaine prevents depotentiation at corticostriatal synapses. Biol Psychiatry. 2006;60:436–443. doi: 10.1016/j.biopsych.2005.11.018. [DOI] [PubMed] [Google Scholar]

RESOURCES