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The Journal of Neuroscience, August 6, 2003, 23(18):7218-7226

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Group III Metabotropic Glutamate Receptor-Mediated Modulation of the Striatopallidal Synapse

Ornella Valenti, Michael J. Marino, Marion Wittmann, Edward Lis, Anthony G. DiLella, Gene G. Kinney, and P. Jeffrey Conn

Department of Neuroscience, Merck Research Laboratories, West Point, Pennsylvania 19486

The globus pallidus (GP) is a key GABAergic nucleus in the basal ganglia (BG). The predominant input to the GP is an inhibitory striatal projection that forms the first synapse in the indirect pathway. The GP GABAergic neurons project to the subthalamic nucleus, providing an inhibitory control of these glutamatergic cells. Given its place within the BG circuit, it is not surprising that alterations in GP firing pattern are postulated to play a role in both normal and pathological motor behavior. Because the inhibitory striatal input to the GP may play an important role in shaping these firing patterns, we set out to determine the role that the group III metabotropic glutamate receptors (GluRs) play in modulating transmission at the striatopallidal synapse. In rat midbrain slices, electrical stimulation of the striatum evoked GABA_A-mediated IPSCs recorded in all three types of GP neurons. The group III mGluR-selective agonist L-(+)-2-amino-4-phosphonobutyric acid (L-AP4) inhibited these IPSCs through a presynaptic mechanism of action. L-AP4 exhibited high potency and a pharmacological profile consistent with mediation by mGluR4. Furthermore, the effect of L-AP4 on striatopallidal transmission was absent in mGluR4 knock-out mice, providing convincing evidence that mGluR4 mediates this effect. The finding that mGluR4 may selectively modulate striatopallidal transmission raises the interesting possibility that activation of mGluR4 could decrease the excessive inhibition of the GP that has been postulated to occur in Parkinson's disease. Consistent with this, we find that intracerebroventricular injections of L-AP4 produce therapeutic benefit in both acute and chronic rodent models of Parkinson's disease.

Key words: basal ganglia; globus pallidus; metabotropic glutamate receptor; mGluR4; Parkinson's disease; synaptic transmission

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Received Jan. 9, 2003; revised Jun. 16, 2003; accepted Jun. 23, 2003.

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