D5 dopamine receptors control glutamatergic AMPA transmission between the motor cortex and subthalamic nucleus

Corticofugal fibers target the subthalamic nucleus (STN), a component nucleus of the basal ganglia, in addition to the striatum, their main input. The cortico-subthalamic, or hyperdirect, pathway, is thought to supplement the cortico-striatal pathways in order to interrupt/change planned actions. To explore the previously unknown properties of the neurons that project to the STN, retrograde and anterograde tools were used to specifically identify them in the motor cortex and selectively stimulate their synapses in the STN. The cortico-subthalamic neurons exhibited very little sag and fired an initial doublet followed by non-adapting action potentials. In the STN, AMPA/kainate synaptic currents had a voltage-dependent conductance, indicative of GluA2-lacking receptors and were partly inhibited by Naspm. AMPA transmission displayed short-term depression, with the exception of a limited bandpass in the 5 to 15 Hz range. AMPA synaptic currents were negatively controlled by dopamine D5 receptors. The reduction in synaptic strength was due to postsynaptic D5 receptors, mediated by a PKA-dependent pathway, but did not involve a modified rectification index. Our data indicated that dopamine, through post-synaptic D5 receptors, limited the cortical drive onto STN neurons in the normal brain.We thank Dr. L. Kerkerian Le Goff and Dr. J.L. Lanciego for helpful discussions on our project. We acknowledge the help of Gilles le Pape (AnaStats, Les Vigneaux, France, www.anastats.fr) for statistical analysis of the neurons' intrinsic parameters and input-output curves. We wish to thank Drs Melanie Ginger and Katy Le Corf, for producing the RabV vector, Dr. Sibley (NINDS, Bethesda), who allowed us to use the D5R mutant mice he engineered, as well as Dr. J. Waddington (Royal College of Surgeons, Dublin), who donated the D5R mutant mice we used to generate a colony. Imaging was performed in the Bordeaux Imaging Center, part of the national FranceBioImaging infrastructure. L.F had a PhD funded by MRT, and received a 6-month fellowship from France Parkinson. The Regional Council of Aquitaine and Fondation de France supported this work by grants 12006005 (FCAN scheme), and 2005013850 and 00016810, respectively. France Parkinson supported part of the work (grant no 5293). Financial support was also provided by CNRS, University of Bordeaux, and Labex Brain (ANR-10-LABX-0043)