The debilitating motor symptoms in Parkinson's disease are related to aberrant spike firing of neurons in the subthalamic nucleus (STN), a key structure within the basal ganglia motor circuit. Glutamatergic afferents to the STN critically regulate STN neuron firing frequency and pattern;however the functions of specific glutamate receptors in mediating synaptic transmission in the STN have not been well-studied. The N-methyl- D-aspartate (NMDA) family of ionotropic glutamate receptors are critical for excitatory neurotransmission throughout the brain. NMDA receptors are tetramers composed of two GluN1 subunits and two GluN2 subunits (GluN2A-2D), and the GluN2 subunits display different functional properties as well as expression patterns in the brain. The GluN2B and GluN2D subunits are expressed by STN neurons, however the lack of GluN2D-selective compounds has limited the study of this subunit in the brain. Newly developed allosteric modulators that are selective for GluN2C/D subunits will now allow investigation of the function of GluN2D in the STN as well as the potential of inhibition of GluN2D-containing NMDA receptors as a therapeutic strategy to correct the aberrant firing of STN neurons in Parkinson's disease. In this study, patch-clamp electrophysiology and optogenetics will be used to investigate the roles of GluN2B- and GluN2D-containing NMDA receptors at the different glutamatergic inputs to the STN.
The specific aims of the proposed work are: 1) how NMDA receptor subtypes control excitatory synaptic transmission at anatomically distinct afferents to the STN, and 2) how specific NMDA receptors control tonic and activity-induced spike firing in STN neurons. These experiments will generate key data on the roles for NMDA receptors in controlling glutamatergic neurotransmission and spike firing in the STN.
In Parkinson's disease, neurons in the subthalamic nucleus display a characteristic firing pattern that contributes to the loss of movement control. Deep brain stimulation of these neurons can alter firing patterns and improve motor symptoms in some patients, however a pharmacological means to alter activity within this brain region is an attractive, non-invasive strategy for treating Parkinson's disease. This work will examine the specific receptors that control activation of the subthalamic nucleus as a first step in evaluating whether modulating these receptors is a potential therapeutic strategy.