Activation of group III mGluRs inhibits GABAergic and glutamatergic transmission in the substantia nigra pars reticulata

The GABAergic projection neurons of the substantia nigra pars reticulata (S Nr) exert an important influence on the initiation and control of movement. The SNr is a primary output nucleus of the basal ganglia (BG) and is contr olled by excitatory inputs from the subthalamic nucleus (STN) and inhibitor y inputs from the striatum and globus pallidus. Changes in the output of th e SNr are believed to be critically involved in the development of a variet y of movement disorders. Anatomical studies reveal that metabotropic glutam ate receptors (mGluRs) are highly expressed throughout the BG. Interestingl y, mRNA for group III mGluRs are highly expressed in STN, striatum, and glo bus pallidus, and immunocytochemical studies have shown that the group III mGluR proteins are present in the SNr. Thus it is possible that group III m GluRs play a role in the modulation of synaptic transmission in this nucleu s. We performed whole cell patch-clamp recordings from nondopaminergic SNr neurons to investigate the effect of group III mGluR activation on excitato ry and inhibitory transmission in the SNr. We report that activation of gro up III mGluRs by the selective agonist L(+)-2-amino-4-phosphonobutyric acid (L-AP4, 100 muM) decreases inhibitory synaptic transmission in the SNr. Mi niature inhibitory postsynaptic currents studies and paired-pulse studies r eveal that this effect is mediated by a presynaptic mechanism. Furthermore we found that L-AP4 (500 muM) also reduces excitatory synaptic transmission at the STN-SNr synapse by action on presynaptically localized group III mG luRs. The finding that mGluRs modulate the major inputs to SNr neurons sugg ests that these receptors may play an important role in motor function and could provide new targets for the development of pharmacological treatments of movement disorders.