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...

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Loss of nigrostriatal dopaminergic neurons in Parkinson's disease (PD) leads to increased activity of glutamatergic neurons in the subthalamic nucleus (STN). Recent studies reveal that the resultant increase in STN-induced excitation of basal ganglia output nuclei is responsible for the disabling motor impairment characteristic of PD. On the basis of this, it is possible that any manipulation that reduces activity at excitatory STN synapses onto basal ganglia output nuclei could be useful in the treatment of PD. We now report that group II metabotropic glutamate receptors (mGluRs) are presynaptically localized on STN terminals and that activation of these receptors inhibits excitatory transmission at STN synapses. In agreement with the hypothesis that this could provide a therapeutic benefit in PD, a selective agonist of group II mGluRs induces a dramatic reversal of catalepsy in a rat model of PD. These results raise the exciting possibility that selective agonists of group II mGluRs could provide an entirely new approach to the treatment of PD. These novel therapeutic agents would provide a noninvasive pharmacological treatment that does not involve the manipulation of dopaminergic systems, thus avoiding the problems associated with current therapies. Key words: substantia nigra pars reticulata; subthalamic nucleus; group II metabotropic glutamate receptors; Parkinson's disease; catalepsy; presynaptic inhibitionParkinson's disease (PD) is a common neurodegenerative disorder characterized by disabling motor impairments including tremor, rigidity, and bradykinesia. The primary pathological change giving rise to the symptoms of PD is the loss of dopaminergic neurons in the substantia nigra pars compacta that modulate the function of neurons in the striatum and other nuclei in the basal ganglia (BG) motor circuit. Currently, the most effective pharmacological agents for the treatment of PD include levodopa (L-DOPA), the immediate precursor of dopamine, and other drugs that replace the lost dopaminergic modulation of BG function (Poewe and Granata, 1997). Unfortunately, dopamine replacement therapy ultimately fails in most patients because of loss of efficacy with progression of the disease and severe motor and psychiatric side effects (Poewe et al., 1986). Because of this, a great deal of effort has been focused on developing new approaches for the treatment of PD.Recent studies reveal that loss of nigrostriatal dopamine neurons results in a series of neurophysiological changes that lead to overactivity of a critical nucleus in the BG motor circuit termed the subthalamic nucleus (STN). The STN contains glutamatergic projection neurons that provide the major excitatory input to the globus pallidus internal segment (GPi) and the substantia nigra pars reticulata (SNr), the major output nuclei of the basal ganglia. Increased activity of STN neurons leads to an increase in glutamate release at STN synapses onto GABAergic projection neurons in the output nuclei. This glutamate-mediated overexcitation of BG output ultima...

Our current understanding of the circuitry of the basal ganglia, and the pathophysiology of Parkinson's disease has led to major breakthroughs in the treatment of this debilitating movement disorder. Unfortunately, there are significant problems with the currently available pharmacological therapies that focus on dopamine replacement or dopaminergic agonists. Because of this, much effort has been focused on developing novel targets for the treatment of Parkinson's disease. The metabotropic glutamate receptors are a family of G-protein coupled receptors activated by glutamate. These receptors are differentially distributed throughout the basal ganglia in a manner suggesting that they may provide novel targets for the treatment of movement disorders. In this review we summarize anatomical and physiological data from our work and the work of other laboratories describing the distribution and physiological roles of metabotropic glutamate receptors in the basal ganglia with emphasis on possible therapeutic targets.

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