Activation of metabotropic glutamate receptor 5 has direct excitatory effects and potentiates NMDA receptor currents in neurons of the subthalamic nucleus

The subthalamic nucleus (STN) is a key nucleus in the basal ganglia motor c ircuit that provides the major glutamatergic excitatory input to the basal ganglia output nuclei. The STN plays an important role in normal motor func tion, as well as in pathological conditions such as Parkinson's disease (PD ) and related disorders. Development of a complete understanding of the rol es of the STN in motor control and the pathophysiological changes in STN th at underlie PD will require a detailed understanding of the mechanisms invo lved in regulation of excitability of STN neurons. Here, we report that act ivation of group I metabotropic glutamate receptors (mGluRs) induces a dire ct excitation of STN neurons that is characterized by depolarization, incre ased firing frequency, and increased burst-firing activity. In addition, ac tivation of group I mGluRs induces a selective potentiation of NMDA-evoked 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. Interesting ly, 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 glutamatergi c afferents. Furthermore, these studies raise the exciting possibility that selective ligands for mGluR5 may provide a novel approach for the treatmen t of a variety of movement disorders that involve changes in STN activity.