Activation of Metabotropic Glutamate Receptor 5 Has Direct Excitatory Effects and Potentiates NMDA Receptor Currents in Neurons of the Subthalamic Nucleus

Abstract

The subthalamic nucleus (STN) is a key nucleus in the basal ganglia motor circuit that provides the major glutamatergic excitatory input to the basal ganglia output nuclei. The STN plays an important role in normal motor function, as well as in pathological conditions such as Parkinson's disease (PD) and related disorders. Development of a complete understanding of the roles of the STN in motor control and the pathophysiological changes in STN that underlie PD will require a detailed understanding of the mechanisms involved in regulation of excitability of STN neurons. Here, we report that activation of group I metabotropic glutamate receptors (mGluRs) induces a direct excitation of STN neurons that is characterized by depolarization, increased firing frequency, and increased burst-firing activity. In addition, activation of group I mGluRs induces a selective potentiation of NMDAevoked currents. Immunohistochemical studies at the light and electron microscopic levels indicate that both subtypes of group I mGluRs (mGluR1a and mGluR5) are localized postsynaptically in the dendrites of STN neurons. Interestingly, pharmacological studies suggest that each of the mGluR-mediated effects is attributable to activation of mGluR5, not mGluR1, despite the presence of both subtypes in STN neurons. These results suggest that mGluR5 may play an important role in the net excitatory drive to the STN from glutamatergic afferents. Furthermore, these studies raise the exciting possibility that selective ligands for mGluR5 may provide a novel approach for the treatment of a variety of movement disorders that involve changes in STN activity. Key words: metabotropic glutamate receptor; subthalamic nucleus; basal ganglia; Parkinson's disease; burst firing; NMDA receptor; mGluR1; mGluR5The basal ganglia (BG) are a set of subcortical nuclei that play a critical role in motor control and are a primary site of pathology in a number of movement disorders, including Parkinson's disease (PD), Tourette's syndrome, and Huntington's disease. Recent studies reveal that a key nucleus in the BG motor circuit, the subthalamic nucleus (STN), plays an especially important role in BG function. The STN is an excitatory glutamatergic nucleus in the BG and provides the major excitatory input to the BG output nuclei, the substantia nigra pars reticulata (SNr) and the internal globus pallidus. Normal motor function requires an intricate balance between excitation of the output nuclei by glutamatergic neurons from the STN and inhibition of the output nuclei by GABAergic projections from the striatum (for review, see Wichmann and DeLong, 1997).Interestingly, recent studies suggest that the major pathophysiological change that occurs in response to loss of nigrostriatal dopamine neurons in PD patients is an increase in activity of STN neurons. The resultant increase in synaptic excitation of GABAergic projection neurons in the output nuclei leads to a "shutdown" of thalamocortical projections and produces the motor impairment characteristic of PD (DeLong, 199...

Functional Interaction Between NMDA and mGlu5 Receptors: Effects on Working Memory, Instrumental Learning, Motor Behaviors, and Dopamine Release

“…The activation of mGlu5 receptors leads to postsynaptic excitatory effects and potentiation of NMDA currents (Bleakman et al, 1992;Conn and Pin, 1997;Bordi and Ugolini, 1999;Awad et al, 2000). NMDA receptors follow a complex mode of regulation, as their activation is voltage dependent, requires additional ligand binding, and is influenced by a number of modulatory sites.…”

“…In the context of NMDA receptor-mediated neurotransmission, the mGlu5 subtype of mGluRs is of special interest. In vitro studies have suggested that activation of mGlu5 receptors, which are coupled via Gq to phospholipase C, can increase NMDAevoked responses in neural tissues including cortex (Doherty et al, 1997;Ugolini et al, 1997;Awad et al, 2000;Attucci et al, 2001;Mannaioni et al, 2001;Pisani et al, 2001). The selective mGlu5 receptor antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) blocks NMDA-induced membrane depolarization in striatal spiny neurons and in cortical wedges (Pisani et al, 1997;Attucci et al, 2001).…”

The Ampakine CX546 Restores the Prepulse Inhibition and Latent Inhibition Deficits in mGluR5-Deficient Mice

“…In the context of NMDAR-mediated neurotransmission, the mGluR5 subtype of mGluRs is of special interest. The mGluR5 binds through G-dependent or independent pathways (Heuss et al, 1999) with predominantly couple via Gq to phospholipase C. This yields diacylglycerol, which activates protein kinase C (PKC), and inositol-1,4,5-triphosphate, which releases intracellular Ca 2 + (Conn and Pin, 1997), and this in turn can increase NMDAR-evoked responses in a variety of neuronal tissues (Doherty et al, 1997;Awad et al, 2000), indicating one potential functional link between mGluR5 and NMDAR. Indeed, administration of mGluR5 antagonist 2-methyl-6-(phenylethynyl)pyradine (MPEP) facilitated in vivo effects of NMDAR antagonists in rodents, producing anxiolytic (Spooren et al, 2000), neuroprotective (Bruno et al, 2000), and anticonvulsant (Chapman et al, 2000) effects, disrupting prepulse inhibition (PPI) (Kinney et al, 2003) and enhancing the detrimental effects of MK-801 on cognition and stereotypy (Homayoun et al, 2004).…”

NMDA-induced potentiation of mGluR5 is mediated by activation of protein phosphatase 2B/calcineurin

“…One prominent effect of mGluR activation in many neuronal populations is an enhancement of agonist-evoked currents through NMDA receptor channels (Aniksztejn et al, 1991;Jones and Headley, 1995;Bleakman et al, 1992;Harvey and Collingridge, 1993;Fitzjohn et al, 1996;Pisani et al, 1997;Awad et al, 2000). In each of these cases, mGluR-induced potentiation of NMDA receptor currents is mediated by a group I mGluR.…”

“…However, the specific group I mGluR subtype involved in eliciting this effect can vary in different neuronal populations. For instance, recent pharmacological studies reveal that potentiation of NMDA-evoked currents is mediated by mGluR5 in hippocampal pyramidal cells (Doherty et al, 1997) (Mannaioni et al, 2001) and in neurons in the subthalamic nucleus (Awad et al, 2000), whereas this response is mediated by mGluR1 in cortical cells (Heidinger et al, 2002).…”