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...