Activation of Group I Metabotropic Glutamate Receptors Produces a Direct Excitation and Disinhibition of GABAergic Projection Neurons in the Substantia Nigra Pars Reticulata

Abstract

A pathological increase in excitatory glutamatergic input to substantia nigra pars reticulata (SNr) from the subthalamic nucleus (STN) is believed to play a key role in the pathophysiology of Parkinson's disease. We present an analysis of the physiological roles that group I metabotropic glutamate receptors (mGluRs) play in regulating SNr functions. Immunocytochemical analysis at the light and electron microscopic levels reveal that both mGuR1a and mGluR5 are localized postsynaptically in the SNr. Consistent with this, activation of group I mGluRs depolarizes SNr GABAergic neurons. Interestingly, although both group I mGluRs (mGluR1 and mGluR5) are expressed in these neurons, the effect is mediated solely by mGluR1. Light presynaptic staining for mGluR1a and mGluR5 was also observed in some terminals forming symmetric synapses and in small unmyelinated axons. Consistent with this, activation of presynaptic mGluR1a and mGluR5 decreases inhibitory transmission in the SNr. The combination of direct excitatory effects and disinhibition induced by activation of group I mGluRs could lead to a large excitation of SNr projection neurons. This suggests that group I mGluRs are likely to play an important role in the powerful excitatory control that the STN exerts on basal ganglia output neurons.

Distinct Functional Roles of the Metabotropic Glutamate Receptors 1 and 5 in the Rat Globus Pallidus

“…It is unlikely that the mGluR5-mediated effects on mGluR1 response described in the present study occur in all neurons that coexpress the two group I mGluR subtypes. For instance, such interactions were not seen in SNr, STN, or hippocampal neurons Mannaioni et al, 2001;Marino et al, 2001). Even in the GP itself, the mGluR5-mediated desensitization of mGluR1 activity was found in type II, but not type I, neurons.…”

“…However, the DHPG-induced depolarization and the potentiation of NMDA receptor currents in the STN is mediated solely by mGluR5, whereas activation of mGluR1 only is responsible for depolarization and induction of a slow EPSP in SNr neurons Marino et al, 2001). Because GP neurons also coexpress both group I mGluR subtypes (Fig.…”

“…Coexpression of both mGluR1a and mGluR5 has been reported in the STN, the SNr, and the striatum, three nuclei of the BG circuitry (Tallaksen-Greene et al, 1998;Awad et al, 2000;Marino et al, 2001). However, the DHPG-induced depolarization and the potentiation of NMDA receptor currents in the STN is mediated solely by mGluR5, whereas activation of mGluR1 only is responsible for depolarization and induction of a slow EPSP in SNr neurons Marino et al, 2001).…”

“…Group I mGluRs are both present in the globus pallidus (GP), the subthalamic nucleus (STN), the substantia nigra pars reticulata (SNr), and the striatum (Tallaksen-Greene et al, 1998;Hanson and Smith, 1999;Awad et al, 2000;Marino et al, 2001) (for review, see Rouse et al, 2000). Metabotropic GluR1 and mGluR5 carry distinct functions in the STN, SNr, and the striatum in which they colocalize to the same neurons (Pisani et al, 2001a;Marino et al, 2002).…”

Parkinson's Disease Therapeutics: New Developments and Challenges Since the Introduction of Levodopa

“…The mGluR5 is heavily distributed postsynaptically in key basal ganglia nuclei, including the striatum, the globus pallidus, and the STN (Hanson and Smith, 1999;Smith et al, 2000Smith et al, , 2001Hubert et al, 2001;Paquet and Smith, 2003;Kuwajima et al, 2004;Conn et al, 2005;Kuwajima et al, 2007;Poisik et al, 2007;Niswender and Conn, 2010). In each of these structures, the localization and physiological properties of this receptor have been carefully studied in rodents and nonhuman primates Awad et al, 2000;Marino et al, 2001;Poisik et al, 2003;Conn et al, 2005;Galvan et al, 2006). mGluR5 activation mediates slow excitatory effects upon basal ganglia nuclei.…”