metabotropic glutamate receptors in the basal ganglia motor circuit

*Program in Translational Neuropharmacology, Department of Pharmacology, Vanderbilt University Medical Center, 23rd Avenue South at Pierce, 417-D Preson Research Building, Nashville, Tennessee 37232-6600, USA. ‡Department of Neuropharmacology, Instituto Neurologico Mediterraneo, Neuromed, Località Camerelle, 86077, Pozzilli, Italy. §Neuroscience Drug Discovery, Movement Disorders, Merck Research Laboratories, WP46-300, 770 Sumneytown Pike, West Point, Pennsylvania 19486, USA. ||Department of Human Physiology and Pharmacology, University of Rome ‘La Sapienza’, Piazzale Aldo Moro 5, 00185, Rome, Italy. Correspondence to J.C. e-mail: [email protected]:10.1038/nrn1763

METABOTROPIC GLUTAMATE RECEPTORS IN THE BASAL GANGLIA MOTOR CIRCUITP. Jeffrey Conn*, Giuseppe Battaglia‡, Michael J. Marino§ and Ferdinando Nicoletti‡||

Abstract | In recent years there have been tremendous advances in our understanding of the circuitry of the basal ganglia and our ability to predict the behavioural effects of specific cellular changes in this circuit on voluntary movement. These advances, combined with a new understanding of the rich distribution and diverse physiological roles of metabotropic glutamate receptors in the basal ganglia, indicate that these receptors might have a key role in motor control and raise the exciting possibility that they might provide therapeutic targets for the treatment of Parkinson’s disease and related disorders.

One of the greatest achievements in the quest to bridge cellular and integrative neuroscience in recent years has been the development of an understanding of the basal ganglia motor circuit, including know-ledge of how activity in this circuit influences motor behaviour and how changes in this circuit give rise to motor dysfunction in diseases such as Parkinson’s disease (PD). This is a rare example of a field in which our understanding at a circuit level began with clinical studies in humans and studies in non-human primates. These findings are now driving studies at the cellular and molecular levels that, in turn, drive further studies at the behavioural and system levels.

One area of this field that has seen tremendous progress during the past few years is our under stan-ding of the roles of a subset of G-protein-coupled receptors (GPCRs), known as metabotropic glutamate receptors (mGluRs), in the regulation of ion channels, synaptic transmission and synaptic plasticity through the basal ganglia motor circuit. The behavioural effects of ligands of specific mGluR subtypes are precisely those predicted from the cellular studies.

Another particularly exciting aspect of this field is that researchers have been able to relate phenomena at the cellular level directly to circuit-level and behav-ioural changes. Moreover, studies in this area have led to the development of new strategies for the treatment

of PD that have stimulated highly focused drug discovery efforts. Also exciting is the possibility, raised by these studies, that ligands of mGluRs might both provide symptomatic relief in patients with PD and reduce the progression of this disorder by exerting a direct neuroprotective effect on dopaminergic neurons. In addition to the advances in the basic biology of basal ganglia function, the drug discovery efforts fuelled by these studies have contributed to the development of new, drug-like molecules that act as allosteric regulators of GPCRs. These compounds have clear advantages over traditional receptor agonists in that they rely on the action of endogenous transmitter released in an activity-dependent manner, whereas traditional receptor agonists bypass the action of the endogenous transmitter and induce tonic activation of receptors.

mGluRs in the basal gangliaThe basal ganglia are an interconnected group of subcortical nuclei that are involved in the control of motor behaviour. The primary input nucleus of the basal ganglia is the neostriatum (caudate nucleus and putamen), and the primary ouput nuclei are the substantia nigra pars reticulata (SNr) and the inter-nal globus pallidus (GPi; entopeduncular nucleus in non-primates). Projection neurons in the neostriatum

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© 2005 Nature Publishing Group

CortexCM thalamus

Cerebral cortex

Caudate-putamen

GPeSNc

STN

GPi/SNr

VA, VL, VM thalamus

GABAACh

DA GABAGABA

GABA

Glut

Glut

mGluR1

mGluR5

mGluR2/3mGluR4

D1(+)

(+)

(–)

(+)

D2(–)

(–)

(–)

send signals to these output nuclei (SNr and GPi) both directly and indirectly through the external globus pallidus (GPe) and the subthalamic nucleus (STN) (FIG. 1). These striatal projection neurons are inhibitory neurons that use the neurotransmitter GABA (γ-aminobutyric acid). Therefore, activity through the ‘direct pathway’ from the striatum to the SNr and GPi provides powerful inhibitory control of these basal ganglia output neurons. By contrast, activity through the parallel ‘indirect pathway’ leads to increased activity of excitatory glutamatergic neurons in the STN, which induces strong excitation of the SNr and GPi (FIG. 1).

A delicate balance of inhibition of output nuclei through the direct pathway and excitation through the indirect pathway is essential for normal motor function. Dopaminergic neurons in the substantia nigra pars compacta (SNc) are crucial for regulating the balance of activity between these two pathways.

Dopamine acts in the striatum to reduce transmission through the indirect pathway and to increase activity through the direct pathway. A disruption in the bal-ance between excitation and inhibition of the output nuclei by the indirect and direct pathways, respectively, is believed to underlie the motor dysfunction in vari-ous motor disorders, including PD and Huntington’s disease (HD)1,2.

The results of recent studies indicate that mGluRs are heavily expressed throughout the basal ganglia, where they have several important functions in regulating neuronal excitability and synaptic trans-mission3,4. The mGluRs include eight subtypes that have been divided into group I (mGluR1 and mGluR5), group II (mGluR2 and mGluR3) and group III (mGluR4, 6, 7 and 8) on the basis of sequence homologies and G-protein coupling5,6 TABLE 1. Members of each of these groups have important roles in regulating activity through the basal ganglia motor circuit (FIG. 1).

As the primary basal ganglia input nucleus, the striatum integrates and processes information from the motor cortex and other sites, such as the thalamus, as well as receiving dopaminergic inputs from the SNc. The integration of these inputs is modulated by at least three types of interneuron, including fast-spiking parvalbumin-containing GABA interneurons; burst firing NADPH diaphorase/somatostatin-positive GABA interneurons; and large aspiny cholinergic interneurons7–11. Group I mGluRs regulate many extrinsic inputs to the striatum as well as intrinsic activity through striatal interneurons.

mGluR1 receptors are expressed by dopaminergic neurons of the SNc12, and their activation can either hyperpolarize13 or depolarize13,14 these neurons, possibly depending on the intensity and duration of mGluR activation. However, a primary response to the stimulation of glutamatergic afferents to SNc dopamine neurons is the induction of inhibitory postsynaptic potentials by increasing a Ca2+-activated K+ conductance13. mGluR1 receptors are also local-ized presynaptically on dopaminergic fibres12, which converge with corticostriatal glutamatergic fibres on the dendritic spines of medium spiny neurons. The glutamate that escapes the confines of corticostriatal synapses activates mGluR1 receptors on nigrostriatal terminals, thereby suppressing dopamine release15. Interestingly, mGluR1a receptors co-immunoprecip-itate and functionally interact with ephrin-B2 in the developing striatum16. Ephrins, by interacting with their cognate Eph receptors, are widely involved in developmental pattering and cell–cell communica-tion. Therefore, interactions between mGluR1 receptors and ephrin-B2 might be involved in sev-eral aspects of developmental plasticity, including correct pathfinding by nigrostriatal dopaminergic axon terminals17,18.

In the striatum, both mGluR1 and mGluR5 recep-tors are expressed by medium spiny GABA neurons, as well as by all interneurons19. In spiny neurons, the activation of mGluR5 receptors amplifies NMDA

Figure 1 | Localization of metabotropic glutamate receptor (mGluR) subtypes in the basal ganglia motor circuit. The figure highlights how dopamine (DA) acting in the neostriatum (caudate nucleus–putamen) influences the activity of the direct and indirect pathways (black and turquoise arrows, respectively). Both pathways converge to regulate the activity of thalamocortical neurons. The activation of D1 dopamine receptors stimulates striatal output neurons of the direct pathway, leading to inhibition of GABA (γ-aminobutyric acid) neurons in the internal globus pallidus (GPi) and substantia nigra pars reticulata (SNr). In the indirect pathway, activation of D2 receptors inhibits striatal output neurons that project to the external globus pallidus (GPe). This results in the sequential inhibition of glutamatergic neurons in the subthalamic nucleus (STN) and GABA neurons in the GPi/SNr. The net effect of group I mGluRs is to counterbalance the action of dopamine across the direct pathway, although both mGluR1 and mGluR5 receptors stimulate GPe neurons. Activation of mGluR2/3 receptors mimics the action of dopamine by reducing glutamate release at corticostriatal and STN–GPi and STN–SNr synapses. mGluR4 receptor activation mimics the action of dopamine in the indirect pathway by inhibiting GABA release at the striatum–GPe synapse. For further information see REFS 12,117,118,145147. ACh, acetylcholine; CM thalamus, thalamic centromedian nucleus; Glut, glutamate; VA, VL, VM thalamus, ventral anterior, ventrolateral and ventromedial thalamic nuclei.

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(N-methyl-d-aspartate) receptor currents20,21, as has been shown in other neurons across the CNS22–24. The activation of NMDA receptors (NMDARs) can also potentiate mGluR5 receptor signalling by limiting receptor desensitization through the activation of the protein phosphatase calcineurin25,26. A tight bidirect-ional interaction between mGluR5 and NMDA recep-tors is made possible by a chain of anchoring proteins (including PSD-95 (from postsynpatic density-95), Shank and Homer) that clusters both receptors in the same synaptic territory27. The combined activation of mGluR5 and NMDA receptors in spiny neurons activates gene expression through rapid and transient phosphorylation of the transcription factors ELK1 (a member of the Ets family) and cyclic AMP (cAMP) responsive element-binding protein (CREB), which results from the activation of the mitogen-activated protein kinase (MAPK) pathway and inhibition of the protein phosphatases 1 and 2A28–30.

Medium spiny neurons that project to the GPe and give rise to the indirect pathway of the basal ganglia are regulated in opposite directions by D2 dopamine (D2R) and A2A adenosine receptors, which are coupled

to Gi and Gs proteins (G-protein subunits), respectively. mGluR5 receptors physically interact with A2A recep-tors and act synergistically with them in promoting a series of downstream events, including the activation of MAPK31,32. Therefore, a ‘ménage a trois’ among A2A, mGluR5 and NMDA receptors counteracts the effect of dopamine on striatal medium spiny neurons of the indirect pathway (FIG. 2a). NMDAR currents are also amplified in these neurons by the acetylcholine that is released by striatal interneurons in response to mGluR1 or mGluR5 receptor activation33–38.

Activation of mGluR1/5 receptors can also affect synaptic responses to dopamine by modulating the activity of the dopamine- and cAMP-regulated phosphoprotein (DARPP-32). Phosphorylation of DARPP-32 by protein kinase A (PKA) on threonine at amino acid position 34 converts DARPP-32 to an inhibitor of protein phosphatase 1, thereby amplifying D1 dopamine receptor signalling. The activation of mGluR1/5 receptors inhibits this pathway by stim -ulating the activity of casein kinase 1 (CK1) and cyclin-dependent kinase 5 (CDK5), which phosphorylate DARPP-32 on Thr75 and serine 137, converting the

Table 1 | mGluRs and implications for the experimental treatment of PD and HD

Group Subtype Signal transduction Effect General comment

I mGluR1mGluR5

Gq PLC Ca2+

Agonist

Gq

Agonist

K+

↑[Ca2+]i, PKC↓IK+

mGluR1 antagonists/negative modulators are potentially neuroprotective in models of HD.Effect on extrapyramidal motor symptoms: uncertain.

mGluR5 antagonists/negative modulators relieve parkinsonian symptoms and protect against nigrostriatal degeneration.Prototype mGluR5 antagonists: MPEP, SIB-1757, SIB-1893.

II mGluR2mGluR3

Gi AC

Agonist

cAMP

ATP

↓cAMP mGluR2/3 agonists/enhancers relieve parkinsonian symptoms and protect against nigrostriatal degeneration.Mechanisms: inhibition of glutamate, release and production of neurotrophic factors.Prototype mGluR2/3 agonists: LY354740, LY379268.

III mGluR4mGluR6mGluR7mGluR8

Gi

Agonist

Ca2+

↓ICa2+ mGluR4 agonists/enhancers relieve parkinsonian symptoms.Mechanism: disinhibition of GPe neurons.Prototype mGluR4 enhancer: (–)-PHCCC.

AC, adenylyl cyclase; [Ca2+]i, intracellular calcium; cAMP, cyclic AMP; GPe, external globus pallidus; HD, Huntington’s disease; ICa2+, calcium current; IK+, potassium current; LY354740, (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid; LY379268, (–)-2-oxa-4-aminobicyclo[3.1.0.]hexane-4,6-dicarboxylate; mGluR1–5, metabotropic glutamate receptor subunits; MPEP, 2-methyl-6-(phenylethynyl)-pyridine; PD, Parkinson’s disease; PHCCC, N-phenyl-7-(hydroxylimino)cyclopropa[b]chromen-1a-carboxamide; PKC, protein kinase C; PLC, phospholipase C; SIB-1757, 6-methyl-2-(phenylazo)-pyridinol; SIB-1893, (E)-2-methyl-6-(2-phenylethenyl)-pyridine.


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mGluR1/5mGluR5 NMDAR D1D2 A2A

PSD-95GKAP

HomerGq Gq

SHANK

Mg2+

ER

PtdIns(4,5)P2

Ins(1,4,5)P3

DAG

PKC

Ca2+AC1

GsGi Gs

cAMP/PKA

cAMP CDK5CK1

CREB

Gene expression

CaMKII/IV

PKA

PP1

P-DARPP-32(Thr75/Ser137)

P-DARPP-32(Thr34)

a b

+

CROSSDESENSITIZATIONCross-desensitization refers to receptor desensitization (the loss of receptor response to agonist activation) that is triggered by the activation of a different type of receptor located in the same cell, which might or might not share the same coupling mechanism.

protein to an inhibitor of PKA39,40 (FIG. 2b). Together, these data indicate that the net effect of group I mGluRs is to counteract dopaminergic transmission in the striatum.

Group I mGluRs also have effects in other basal ganglia nuclei that could increase activity through the indirect pathway, thereby counteracting the overall effect of dopamine on this circuit. For instance, group I mGluRs increase neuronal excitability in the GPe, STN and SNr. In GPe neurons, application of the mGluR1/5 receptor agonist 3,5-dihydroxyphenylglycine (DHPG) produces two effects: direct membrane depolarization, and inhibition of N- or P-type calcium channels38,41. The former effect is entirely mediated by mGluR1 recep-tors. Interestingly, however, pharmacological blockade of mGluR5 receptors amplifies DHPG-induced neuro-nal depolarization by limiting CROSSDESENSITIZATION between mGluR1 and mGluR5 receptors38. In STN neurons, the activation of mGluR5 receptors induces membrane depolarization and an increase in burst firing42,43, whereas the activation of presynaptic mGluR1 receptors reduces excitatory neurotransmis-sion44. Finally, excitatory neurotransmission at the synapses between STN and SNr neurons is mediated by mGluR1 receptors, whereas both mGluR1 and mGluR5 receptors are localized on inhibitory nerve terminals in the SNr, where they negatively modulate GABA release45. It is interesting to consider these combined actions of group I mGluRs in relation to

the influence of dopamine on this circuit. Dopamine reduces net activity through the indirect pathway, whereas activation of group I mGluRs in each of the main nuclei of the basal ganglia increases activity through the indirect pathway. Furthermore, group I mGluR-induced reduction of transmission at inhibi-tory synapses in the SNr reduces activity in the direct pathway. So, group I mGluRs act at all levels of the basal ganglia circuit to oppose the regulatory effects of dopamine.

The group II mGluRs (mGluR2 and mGluR3) also help to regulate transmission through the basal ganglia circuit. In the striatum, mGluR2 and mGluR3 receptors are presynaptically localized on cortico striatal fibres, where they inhibit glutamate release46–49. mGluR2/3 receptors are localized in the pre-terminal region of the axon and are activated by the extrasynaptic glutamate that is released by the specific amino acid transporter protein that trans-ports glutamate from an intracellular to extracellular compartment while transporting cysteine from the extracellular to intracellular space50. Extrasynaptic glutamate can also suppress dopamine release by interacting with mGluR2/3 receptors on nigrostriatal terminals50. Furthermore, the activation of group II mGluRs reduces transmission at excitatory synapses onto dopamine neurons51. These combined actions could reduce the regulation of striatal function by dopamine. However, systemic injection of the potent

Figure 2 | Functional interactions between group I metabotropic glutamate receptors (mGluRs) and dopamine receptors in striatal neurons. a | mGluR5 receptors, A2A receptors and NMDA (N-methyl-D-aspartate) receptors (NMDARs) act synergistically to counteract D2 dopamine receptor signalling in striato-pallidal neurons of the indirect pathway31,32. Note that mGluR5 and NMDA receptors are physically linked by a chain of anchoring proteins. AC1, adenylyl cyclase type 1; CaMKII/IV, calcium/calmodulin-dependent protein kinase type II/IV; cAMP, cyclic AMP; CREB, cAMP responsive element-binding protein; DAG, diacylglycerol; ER, endoplasmic reticulum; GKAP, guanylate-kinase-associated protein; Gi, Gq, Gs, G proteins; Ins(1,4,5)P3, inositol 1,4,5-trisphosphate; PKA/C, protein kinase A/C; PSD-95, from postsynaptic density 95; PtdIns(4,5)P2, phosphatidylinositol-4,5-bisphosphate; SHANK, from SH3 and multiple ankyrin repeat domains. b | mGluR1/5 receptor activation negatively modulates D1 dopamine receptor signalling by converting dopamine- and cAMP-regulated phosphoprotein 32 (DARPP-32) into a PKA inhibitor39,40. CK1, casein kinase 1; CDK5, cyclin-dependent kinase 5; P-DARPP-32, phosphorylated DARPP-32; PP1, protein phosphatase 1.


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mGluR2/3 receptor agonist (–)-2-oxa-4-aminobicyclo[3.1.0.]hexane-4,6-dicarboxylate (LY379268) enhances dopamine release in the striatum52. The overall role of group II mGluRs in regulating dopaminergic function is, therefore, unclear. One of the most important functions of group II mGluRs in the basal ganglia motor circuit might be at the STN–SNr synapse, where activation of mGluR2/3 receptors inhibits excitatory transmission53. This action would reduce excitatory drive from the indirect pathway to the basal ganglia output nuclei. Group II mGluR activation could, therefore, have a similar effect to that of dopamine on overall transmission through the indirect pathway, although it exerts this effect at the final synapse of this circuit, which is well downstream of the striatum, where dopamine acts.

The group III mGluR subtypes, mGluR4 and mGluR7, are presynaptically localized in the basal ganglia, and negatively modulate both glutamate and GABA release54–56. One of the most important func-tions of group III mGluRs might occur at the striato-pallidal synapse, where activation of presynaptic mGluR4 receptors suppresses GABA transmission56. This is the first synapse in the indirect pathway and is thought to be heavily regulated by striatal dopamine. So, mGluR4 receptor activation might act downstream of dopamine neurons, exerting a dopamine-like effect by reducing transmission at this synapse. Group III mGluRs also reduce transmission in the direct path-way by reducing GABA release in the SNr57. However, this is probably mediated by mGluR7 receptors, which raises the possibility that different group III mGluR subtypes might have predominant roles in reg-ulating transmission through the direct and indirect pathways.

mGluRs in striatal plasticityLong-term changes in synaptic efficacy in the stria-tum underlie motor learning and ‘habit memory’, and the flexibility of synaptic plasticity allows motor habits to be changed in relation to processes of asso-ciative learning19. These mechanisms are probably disrupted in pathological conditions, resulting in the compulsive execution of stereotyped, purposeless movements, for example, those seen in HD, Gilles de la Tourette’s syndrome and levodopa (L-DOPA)-induced dyskinesias19. Pathological changes in striatal synaptic plasticity might also underlie the compulsive use of psychostimulants and other drugs of abuse in addiction58.

A great deal is known about the trans-synaptic and intracellular mechanisms that underlie the long-term depression (LTD) and long-term potentiation (LTP) of excitatory neurotransmission at corticostriatal synapses. LTD is induced by an increase in intra-cellular Ca2+ and requires the co-activation of D1 and D2 dopamine receptors59–61. The combined use of subtype-selective antagonists and knockout mice has shown that LTD induction at corticostriatal syn-apses requires the activation of mGluR1 receptors62–64. The activation of postsynaptic mGluR1 receptors

might lead to intracellular Ca2+ release, activation of protein kinase C (PKC) and formation of endocannabi-noids, all of which are crucial for LTD induction60,65,66. The activation of mGluR2/3 receptors depresses exci-tatory synaptic transmission and is required for the induction of LTD in the dorsal striatum64.

In contrast to LTD induction, the induction of LTP in striatal neurons is mediated by the entry of Ca2+ through NMDAR channels and requires the activa-tion of D1 receptors, but is negatively modulated by D2 receptors19,67. Activation of both mGluR1 and mGluR5 receptors is necessary for LTP in the striatum. These receptors might directly amplify NMDAR cur-rents in the dendritic spines of medium spiny neurons (see above), or might act on aspiny interneurons to stimulate the release of acetylcholine, which, in turn, facilitates NMDAR responses by activating muscarinic receptors19. The involvement of mGluR1 receptors in the pathological form of LTP that is induced by 3-nitropropionic acid (3-NP)19,68–75 is discussed below in relation to the pathophysiology of HD.

Treatments for Parkinson’s diseaseStudies of the roles of mGluRs in regulating basal ganglia function have direct implications for the potential use of ligands of these receptors to treat basal ganglia disorders such as PD. PD is a common neurodegenerative disorder that is characterized by disabling motor impairments such as tremor, rigidity and bradykinesia. The primary pathological change that gives rise to the symptoms of PD is the loss from the SNc of dopaminergic neurons that project to the striatum to regulate activity through the direct and indirect pathways of the basal ganglia (FIG. 1). As discussed, dopamine induces a net reduction in activity through the indirect pathway relative to the direct pathway and thereby acts at the level of the striatum to reduce the overall activity of neurons in the basal ganglia output nuclei (SNr and GPi). The most effective pharmacological agents for the treatment of PD include L-DOPA, the immediate precursor of dopamine, and other drugs that replace the lost dopaminergic modulation of basal ganglia function.

Unfortunately, dopamine replacement therapy ultimately fails in most patients owing to loss of effi-cacy as the disease progresses, as well as severe motor and psychiatric side effects76. D2 dopamine receptor agonists and anticholinergic drugs are alternative options to L-DOPA, but their use is limited by rela-tively low efficacy and severe adverse effects. One important drawback of dopaminergic and anti-cholinergic drugs is that their action is anatomically restricted to the caudate–putamen, which has under-gone severe pathological changes in patients with PD as a result of nigrostriatal cell loss. It is possible that agents that act at various sites downstream of dopamine neurons in the basal ganglia to reduce the increased activity in the indirect pathway could pro-vide anti-parkinsonian effects without the problems associated with dopamine replacement therapies.


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CIRCLING BEHAVIOURRotational behaviour induced by systemic administration of dopaminergic drugs to rodents with unilateral lesions of the nigrostriatal pathway or by unilateral infusion of drugs into different nuclei of the basal ganglia motor circuit. In the classical model of 6-hydroxydopamine-induced degeneration of the nigrostriatal pathway, dopamine receptor agonists (for example, apomorphine) induce contralateral circling, whereas drugs that stimulate dopamine release (for example, amphetamines) induce ipsilateral circling.

The utility of manipulations of the indirect pathway for treatment of patients with PD has been directly validated in clinical studies that have shown that lesions or high frequency stimulation of the STN or the GPi provide a therapeutic benefit to patients with PD77,78. Unfortunately, these surgical approaches are not widely available. However, our new under-standing of the roles of mGluRs in regulating basal ganglia function raises the exciting possibility that these receptors could provide targets for novel phar-macological agents that could reduce transmission through the indirect pathway.

As outlined above, activation of group I mGluRs has effects throughout the basal ganglia that counter-act the overall effect of dopamine. Consistent with the cellular studies, direct injection of group I mGluR agonists in the striatum of rats selectively activates the indirect pathway and reduces motor function79,80. Furthermore, several studies indicate that anta gonists of the mGluR5 receptor have anti-parkinsonian effects in animal models. mGluR5 receptors are effi-ciently inhibited by a series of phenylpyridine deriva-tives (2-methyl-6-(phenylethynyl)-pyridine (MPEP), 6-methyl-2-(phenylazo)-pyridinol (SIB-1757) and (E)-2-methyl-6-(2-phenylethenyl)-pyridine (SIB-1893), which are systemically active. These drugs behave as negative allosteric modulators that block mGluR5 receptors independently of the concentrations of ambient glutamate81,82.

Treatment with MPEP has little effect on amp-hetamine-induced increases in locomotor activity in the unilateral 6-hydroxydopamine rat model of parkin-sonism83. In these unilaterally lesioned rats, ampheta-mine preferentially increases dopaminergic function in the non-lesioned hemisphere and thereby induces a characteristic CIRCLING BEHAVIOUR. Because this model measures a stimulant response rather than akinesia or other parkinsonian effects, it does not provide a measure of anti-parkinsonian effects. However, MPEP alleviates bradykinesia when chronically injected in animals with bilateral nigrostriatal lesions84–86. In rats treated with the dopamine receptor antagonist haloperidol, MPEP reverses the enhancement of striatal pro-enkephalin expression, which reflects pathological hyperactivity of striato-pallidal neurons of the indirect pathway87. Interestingly, MPEP acts synergistically with A2A adenosine receptor antagonists in relieving bradykinesia and reducing the reaction time in rats with bilateral nigrostriatal lesions86, which is consistent with the functional interaction between mGluR5 and A2A receptors in regulating the activity of striato-pallidal neurons (see above). Blockade of mGluR5 receptors might relieve motor dysfunction associated with par-kinsonism by acting at different levels along the basal ganglia circuits, including reducing mGluR5 receptor-mediated excitation of STN neurons43 and amplifying the mGluR1 receptor-mediated excitation of inhibitory GPe neurons that project to the STN38. mGluR5 recep-tor blockade might also reduce the activity of striatal cholinergic interneurons88, thereby mimicking the effect of anticholinergic drugs.

Selective antagonists of mGluR1 receptors have not been rigorously tested in animal models of PD. It is possible that mGluR1 receptor antagonists could also produce anti-parkinsonian effects by acting in the striatum or the SNr (see above). It is also possible that combined blockade of mGluR1 and mGluR5 receptors could have a greater anti-parkinsonian effect than either alone. Interestingly, recent studies reveal that group I mGluRs undergo tremendous plasticity in parkinsonian animals. For instance, only mGluR5 receptors are involved in excitation of STN neurons in control animals, whereas both mGluR1 and mGluR5 receptors excite these cells in parkin-sonian animals89. Conversely, only mGluR1 receptor activation excites SNr neurons in normal animals, whereas both mGluR1 and mGluR5 receptors have excitatory effects in these cells under conditions of dopamine depletion or blockade89. These findings imply that the two receptor subtypes might have redundant roles in the basal ganglia of parkinsonian animals. If so, simultaneous blockade of both mGluR1 and mGluR5 receptors might be required for maximal anti-parkinsonian activity.

The activation of mGluR2/3 receptors would also be predicted to have anti-parkinsonian effects by reducing transmission at corticostriatal and STN–SNr synapses90,91, although receptor agonists might also reduce acetylcholine release in the striatum36,92. (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740) and LY379268 are systemically active selective agonists of mGluR2/3 receptors93. Consistent with studies of group II mGluR actions in the basal ganglia, LY354740 decreases haloperidol-induced muscle rigidity and catalepsy90,94, and intracerebro-ventricular or intranigral injection of LY379268 or (2S,2′R,3′R)-2-(2′,3′-dicarboxycyclopropyl)glycine(DCG-IV; another mGluR2/3 receptor agonist) reverses reserpine-induced akinesia95,96.

Interestingly, 6-hydroxydopamine lesions increase the potency of mGluR2/3 receptor agonists in depressing corticostriatal transmission, an effect that is reversed by chronic L-DOPA treatment97. By contrast, dopamine depletion reduces the effects of group II mGluR agonists at the STN–SNr synapse98. The activity of group II mGluRs might, therefore, be significantly altered in patients with PD. Because of these differential effects of dopamine depletion on mGluR2 receptor function at different sites in the basal ganglia, the effects of mGluR2 receptor ago-nists could be increased in the striatum but reduced overall owing to the loss of activity at the STN–SNr synapse in a chronic parkinsonian state. Consistent with this, group II mGluR agonists were less effective in reducing motor dysfunction in chronic models of PD96 than in acute haloperidol-induced catalepsy90. Although this might reduce the overall utility of group II mGluR agonists for the treatment of PD, it provides an exciting example of the ability to predict behavioural responses to drugs in models of PD on the basis of their electrophysiological effects in the basal ganglia.


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One of the most exciting cellular effects of mGluR ligands in terms of potential new approaches for treat-ing PD is the ability of mGluR4 receptors to reduce transmission at the striato-pallidal synapse55,56. Reduced transmission at this synapse should reduce the activity of STN and SNr neurons and thereby counteract the effect of loss of dopaminergic control of the indirect pathway. In addition, unlike other mGluR responses, the function of mGluR4 receptors at this synapse is not altered in dopamine-depleted animals56. Consistent with the effects of mGluR4 receptor activation at this synapse, intracerebro-ventricular injection of L-2-amino-4-phosphono-butanoate (L-AP4), a drug that selectively activates group III mGluRs (mGluR4, 6, 7 and 8), has a marked anti-parkinsonian effect in various animal models and is as efficacious as L-DOPA in decreas-ing forelimb asymmetry in rats with unilateral 6-hydroxydopamine lesions56,99.

Although the potential for developing mGluR4 receptor agonists for treating PD is exciting, it has been difficult to develop agonists that are highly selective for the mGluR4 receptor. Another approach to receptor activation that has been successful for ligand-gated ion channels is the development of allosteric potentiators of receptor function. Allosteric potentiators do not bind directly to the neurotrans-mitter binding site but bind to another site on the receptor to potentiate the effects of a traditional ago-nist. A classical example of this approach is the use of benzodiazepines (diazepam and related compounds) to potentiate GABAA (GABA type A) receptor func-tion. Allosteric potentiators can have significant advantages over direct-acting agonists because they require the endogenous agonist for activity and thereby maintain the activity-dependence of receptor activation. Recently, N-phenyl-7-(hydroxylimino) cyclopropa[b]chromen-1a-carboxamide (PHCCC) was identified as a selective allosteric potentiator for the mGluR4 receptor, with no direct agonist activity and no potentiator activity at any other mGluR subtype100,101. Interestingly, PHCCC potentiates the effect of L-AP4-induced inhibition of transmission at the striato-pallidal synapse, and produces a marked reversal of reserpine-induced akinesia in rats100. The demonstration that allosteric ligands of GPCRs have potential therapeutic effects represents an impor-tant breakthrough in our approach to regulation of this important class of drug targets. The finding that allosteric antagonists (MPEP) and potentiators (PHCCC) of mGluRs have robust anti-parkinsonian activity provides an exciting example of the poten-tial utility of this approach for the discovery of new therapeutic agents.

Neuroprotection by mGluR ligandsExperimental models of parkinsonism. As well as having potential for the symptomatic treatment of PD, ligands of mGluRs might also be able to reduce the death of dopaminergic cells and thereby slow progression of this disorder. The progressive loss of

neurons in the SNc and other pigmented nuclei of the brainstem in PD probably results from various proc-esses, including increased formation of intracellular oxidant species and impairment of the ubiquitin–proteasome pathway102–104. Despite extensive research, no current treatments have clearly established neuro-protective effects or can reduce the progression of PD. Recent studies have raised the possibility that reducing transmission through the indirect pathway might slow the progressive loss of dopaminergic neurons that occurs in PD. Excitotoxic mechanisms contribute to oxidative damage of nigral neurons, as shown by the protective action of NMDAR antago-nists against nigrostriatal damage in experimental models of parkinsonism105–110. Interestingly, activity through the indirect pathway might contribute to the excitotoxic damage to SNc neurons. In addition to sending glutamatergic projections to the basal ganglia output nuclei, glutamatergic neurons of the STN also project onto the dopaminergic neurons in the SNc. The results of several studies suggest that excitatory drive from the STN might contribute to the loss of dopamine neurons in animal models that show a relatively slow, progressive loss of dopamine neurons110,111. On the basis of these data, it is possible that mGluR ligands that reduce transmission through the indirect pathway could also reduce dopamine cell loss. Furthermore, mGluR ligands might have direct effects on dopamine neurons that reduce excitotoxic damage to these cells.

Consistent with the hypothesis that inhibition of mGluR5 receptors could reduce the death of dopamine neurons, mice treated with mGluR5 receptor antago-nists (MPEP or SIB-1893) or lacking mGluR5 receptors show increased survival of nigrostriatal dopaminergic neurons after administration of the dopaminergic neuro toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine (MPTP)112,113. mGluR5 receptor antagonists are also protective in the methamphetamine model of parkinsonism114 (FIG. 3). Methamphetamine damages striatal dopaminergic terminals in mice115, and, in chronic users, induces neuropathological lesions of the basal ganglia that resemble those seen in PD116. Although the precise mechanisms of the neuroprotec-tive effects of mGluR5 receptor antagonists are not known, blocking or deleting mGluR5 receptors in the STN would be expected to reduce excitatory drive to the SNc, thereby limiting excitotoxicity. It is also pos-sible that combined activation of mGluR5 and NMDA receptors in nigral neurons117,118 or in striatal dopamin-ergic terminals119 is translated into a death signal under conditions of mitochondrial impairment (such as in the presence of the 1-methyl-4-phenylpyridinium ion (MPP+)) or oxidative stress. Blockade of mGluR5 receptors in SNc neurons might contribute to the neu-roprotective effect of mGluR5 receptor antagonists by isolating the NMDAR from its partner and reducing NMDAR-induced cell death (FIG. 3).

Pharmacological activation of mGluR2/3 recep-tors also protects nigrostriatal dopaminergic neurons against toxicity induced by intrastriatal infusion of


R E V I E W S


Production oftrophic factors

Inhibition ofglutamate release

PSD-95GKAP

HomerSHANK

Ca2+

ER

PtdIns(4,5)P2

Ins(1,4,5)P3

DAG

ROS

METHMPP+

MPP+

DA

METH DA

DATDAT

DA

Complex I

NMDAR mGluR5

Glial mGluR3Presynaptic mGluR2/3

DAT

TH

MPTP mGluR5–/–MPTP mGluR5+/+ MPTP MPEPControl

a

b

Neurodegeneration

MPP+ REFS 120,121 or systemic injection of MPTP122. Again, activation of group II mGluRs would be expected to reduce excitatory drive to SNc neurons by reducing transmission at the STN–SNc synapse51. In addition, activation of group II mGluRs induces increased production of neuroprotective factors such as brain-derived neurotrophic factor (BDNF)120

or transforming growth factor-β (TGFβ)123–125 by microglia or astrocytes, respectively (FIG. 3). The latter mechanism is pharmacologically relevant because glial mGluR2/3 receptors do not face the synaptic cleft126 and might not be saturated by endo genous glutamate. Unlike mGluR5 receptor antagonists, mGluR2/3 receptor agonists have no effect on methamphetamine-induced neurotoxicity112.

The neuroprotective effects of mGluR4 receptor ligands in animal models of dopamine cell death have not been tested. However, the cellular effects of mGluR4 receptor activation indicate that activators of this receptor might have a greater neuroprotective effect than activators of other mGluR subtypes. Activation of mGluR4 receptors has a profound effect on transmission through the indirect pathway and induces a more robust acute anti-parkinsonian effect than either mGluR5 receptor antagonists or mGluR2/3 receptor agonists37,56. Furthermore, as well as its effect at the synapse from the striatum to the GPe, activation of mGluR4 receptors directly reduces transmission at excitatory synapses onto SNc dopaminergic neurons127. In addition to its actions in the indirect pathway, activation of mGluR4 receptors on glia inhibits formation of the chemokine RANTES (an acronym for regulated on activation, normal T expressed and secreted)128, which is involved in neuroinflammation in some neurodegenerative disorders. Finally, mGluR4 receptor activation has direct neuroprotective effects on neurons129–131. These combined actions of mGluR4 receptor activation could greatly reduce the loss of dopamine neurons in patients with PD. Therefore, it will be important to determine the effects of mGluR4 receptor activa-tors in animal models of PD when systemically active mGluR4 receptor agonists or allosteric potentiators become available.

Experimental models of Huntington’s disease. There is considerable evidence that mGluRs might also pro-tect striatal medium spiny neurons against excitotoxic damage. Selective loss of this neuronal population occurs in HD, a progressive and fatal disorder that is characterized by choreiform movements and is caused by an expansion of a trinucleotide CAG repeat in the gene that encodes the protein huntingtin (for a review, see REF. 132). Recent studies have shown that mGluR1 and mGluR5 receptor antagonists and mGluR2/3 receptor agonists protect striatal neurons against striatal toxicity induced by NMDA or quinolinic acid (an endogenous NMDAR agonist)125,133–136. A permis-sive role for mGluR1 and/or mGluR5 receptors in NMDA toxicity could explain why the integrity of cortico striatal glutamatergic pathways is required for the induction of striatal neuronal damage by quinolinic acid137. mGluR1 receptor antagonists, but not mGluR5 receptor antagonists135, protect striatal neurons by enhancing GABA release FIG. 4. One of the features of HD is an impairment of complex II of the mitochon-drial respiratory chain (succinate dehydrogenase)138, which can be reproduced experimentally using the

Figure 3 | Metabotropic glutamate receptors (mGluRs) and Parkinson’s disease.a | Shows the influence of mGluR5 and mGluR2/3 receptors on nigrostriatal degeneration in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and methamphetamine (METH) models of parkinsonism. MPTP (the active metabolite of which is 1-methyl-4-phenylpyridinium (MPP+)) and METH damage nigrostriatal neurons through different mechanisms that converge on the production of reactive oxygen species (ROS). Endogenous activation of mGluR5 receptors might contribute to ROS formation by facilitating the activity of NMDA (N-methyl-D-aspartate) receptors (NMDARs) through anchoring proteins and stimulating intracellular calcium release111–114. Activation of group II mGluRs (mGluR2/3) protects nigrostriatal neurons against MPTP toxicity by inhibiting glutamate release and/or increasing the production of neurotrophic factors in glial cells120–125. DA, dopamine; DAG, diacylglycerol; DAT, dopamine transporter; ER, endoplasmic reticulum; GKAP, guanylate-kinase-associated protein; Ins(1,4,5)P3, inositol 1,4,5-trisphosphate; PSD-95, from postsynaptic density 95; PtdIns(4,5)P2, phosphatidylinositol-4,5-bisphosphate; SHANK, from SH3 and multiple ankyrin repeat domains. b | Histological panels show tyrosine hydroxylase (TH) and dopamine transporter (DAT) immunostaining in the substantia nigra of control mice, wild-type mice treated with MPTP, wild-type mice treated with MPTP + MPEP (2-methyl-6-(phenylethynyl)-pyridine), and mGluR5–/– mice treated with MPTP, demonstrating the loss of TH+ cells after treatment with MPTP and their protection by inhibition or lack of mGluR5 receptors. Panel b modified, with permission, from REF. 112 © (2004) Society for Neuroscience.


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mGluR1 mGluR1 mGluR5

Glial mGluR3Presynaptic mGluR2/3

Inhibition ofGABA release

Facilitation ofNMDARs

Induction ofpathological LTP

Production oftrophic factors

Inhibition ofglutamate realese

Neurodegeneration

mitochondrial toxins 3-NP or malonic acid69,139,140. A link between mitochondrial dysfunction and the excitotoxic hypothesis of HD is supported by the find-ing that 3-NP and methylmalonic acid induce a patho-logical form of corticostriatal LTP, which is expressed as selective potentiation of synaptic responses medi-ated by NMDARs. This pathological form of synaptic potentiation might underlie long-term disruption of motor programs as well as the excitotoxic death of medium spiny neurons19. As opposed to induction of physiological LTP, induction of 3-NP-LTP requires the selective activation of mGluR1 receptors, which might act synergistically with D2 receptors to trig-ger events that include the activation of the MAPK pathway19,68,73–75. This indicates that mGluR1 receptor antagonists are potential candidates for the experi-mental treatment of HD FIG. 4. Antisense-induced knockdown of mGluR5 receptors also protects against malonic acid lesions in the rat striatum141, which sup-ports the idea that mGluR5 receptor antagonists might be beneficial in HD (FIG. 4).

The study of mGluRs has been extended to the R6/2 transgenic mouse model of HD, which expresses a small amino-terminal fragment of human huntingtin with about 150 CAG repeats. These mice have been widely used in preclinical drug studies because they survive only three months and therefore allow accu-rate survival studies132. Striatal group II mGluRs are reduced in these mice before the onset of clinical symptoms142. Systemic treatment of R6/2 mice with the mGluR5 receptor antagonist MPEP or the mGluR2/3 receptor agonist LY379268 increases lifespan by about 2 weeks143, and treatment with MPEP (but not with

LY379268) attenuates the progressive decline in motor coordination143. However, neither drug influences the formation of intranuclear inclusions in the striatum of these animals. Note that R6/2 mice are not an ideal model for HD because they are relatively resistant to excitotoxic death and show little neuronal loss. It will be interesting to investigate the effect of mGluR ligands in mice expressing full-length human hunt-ingtin with expanded CAG repeats, which show more striking behavioural abnormalities and degeneration of striatal neurons132.

ConclusionRecent advances in our understanding of mGluRs in the basal ganglia motor circuit reflect the power of combining a broad understanding of the brain circuits involved in controlling specific behavioural responses with detailed analysis of the neurotrans-mitter, receptor and signalling mechanisms that are involved in modulating that circuit. These exciting advances are further refining our understanding of basal ganglia function and stimulating focused drug discovery programmes that might lead to funda-mental advances in our ability to treat basal ganglia disorders. mGluR ligands might be better than iono-tropic glutamate receptor ligands because mGluRs modulate, rather than mediate, excitatory synaptic transmission. Therefore, mGluR ligands are predicted to lack the side effects that result from the inhibition of excitatory synaptic transmission, such as sedation and cognition impairment144.

Clearly, we are just beginning to understand the details of the roles of mGluRs in regulating this circuit and have little information about the precise roles of receptors activated by endogenous gluta-mate in a physiological context. Future studies will be required to clarify how these receptors regulate basal ganglia function under normal physiological and pathophysiological conditions. In addition, we are only beginning to explore the effects of mGluR ligands in animal models of basal ganglia disorders such as PD. In cases in which the behavioural effects of mGluR ligands have been tested, there is a remark-able agreement between behavioural effects in rodent models of PD and what is predicted from cellular studies. However, in some cases, optimal pharma-cological agents are not available, which makes it impossible to fully test the hypotheses generated from cellular studies in vivo.

As new tools become available this will be a high priority for future research. In addition, it will be important to move away from exclusive reliance on rodent models and to test these compounds in parkinsonian monkeys, which are thought to reflect the human disorder more accurately. Finally, the pre-dicted neuroprotective effect of some mGluR ligands remains hypothetical and has not been rigorously tested. It will be crucial to determine whether mGluR ligands have the predicted neuroprotective effects before deciding whether to develop compounds with this activity that can be used for clinical studies.

Figure 4 | Metabotropic glutamate receptors (mGluRs) and Huntington’s disease. Shows the influence of mGluR1/5 and mGluR2/3 receptors on the degeneration of striatal medium spiny neurons in experimental models of Huntington’s disase. mGluR1 receptor activation facilitates excitotoxic neuronal death by inhibiting GABA (γ-aminobutyric acid) release135 or by contributing to the induction of pathological long-term potentiation (LTP)19,68,73–75. mGluR5 receptor activation facilitates toxicity induced by NMDA (N-methyl-D-aspartate) or quinolinic acid by facilitating the activation of NMDA receptors (NMDARs)136,137. mGluR2/3 receptor agonists protect striatal neurons against NMDA and quinolinic acid toxicity137.


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AcknowledgementsWork in P.J.C.’s laboratory is supported by grants from the National Institutes of Health (National Institute of Neurological Disorders and Stroke, NINDS, and National Institute of Mental Health, NIMH) and the Michael J. Fox Foundation.

Competing interests statementThe authors declare no competing financial interests.

Online links

DATABASESThe following terms in this article are linked online to:Entrez Gene: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=geneA2A adenosine receptor | CDK5 | CREB | DARPP-32 | D2R | ELK1 | Homer | PSD-95 | ShankOMIM: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIMHuntington’s disease | Parkinson’s disease

FURTHER INFORMATIONConn’s laboratory: http://pharmacology.mc.vanderbilt.edu/Faculty/Conn_Lab/index.htmAccess to this interactive links box is free online.


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