The STn-SNc hyperdirect pathway modulates dopaminergic neuron activity by inhibiting GABAergic inputs from the SNr via endocannabinoids

Abstract

The hyperdirect pathway of the basal ganglia circuitry terminates with a glutamatergic projection from the Subthalamic Nucleus (STN) to the Substantia Nigra pars compacta (SNc). We recently showed that glutamate released in the SNc drives endocannabinoid production in dopaminergic neurons, which in turn inhibits GABAergic transmission in that region. The present study investigated the potential role of STN glutamatergic projections of the hyperdirect pathway in this novel endocannabinoid modulatory mechanism. Whole-cell patch-clamp recordings were made from SNc dopaminergic neurons in horizontal brain slices (rat) containing STN, SNc and Substantia Nigra pars reticulata (SNr) regions. Either electrical (bi-polar electrode) or pharmacological (local carbachol application) stimulation of the STN was performed to evoke selective glutamate release from terminals in the SNc. GABAergic inputs to the SNc from the SNr were electrically stimulated to evoke inhibitory post-synaptic currents (eIPSCs). Single-pulse electrical stimulation of the STN caused transient (< 1 sec) attenuation of GABAergic eIPSCs amplitudes recorded from dopaminergic neurons (to 73% of control). The eIPSC attenuation was prevented by block of either cannabinoid CB1 receptors with rimonabant (3 µM) or metabotropic glutamate mGluR1 receptors with CPCCOEt (100 µM). Pharmacological activation of STN neurons by rapid local perfusion of muscarinic agonist carbachol (100 µM, 10 s) caused a similar attenuation of eIPSC amplitude. These findings show that glutamate release from STN terminals in the SNc modulates GABAergic transmission through endocannabinoid signalling – a previously undescribed function of the hyperdirect pathway.