Properties and function of lateral inhibition in the globus pallidus – LatInhGP

Parkinson's disease, which is caused by the degeneration of dopamine neurons in the substantia nigra pars compacta affects more than 4 million people worldwide and is characterized by bradykinesia, rigidity and resting tremor. The Basal Ganglia (BG) are a group of subcortical nuclei involved in motor control and movement related disorders. Within the BG, the GABAergic globus pallidus (GP) occupies a critical position through its widespread projections to the entire network. Furthermore, emergence of abnormal synchronised rhythmic bursting in the GP is associated with akinesia and resting tremor in Parkinson's disease (PD). Therefore, understanding the origin of the synchronization and rhythmic oscillations in this nucleus is of particular interest. The GP can be subdivided in two main populations of GABAergic neurons which express either enkephalin (GP-ENK) or parvalbumin (GP-PV). GP neurons control each other's activity via axon collaterals, but the nature of the interactions between these two populations remains elusive. In addition, GABAergic GP neurons are reciprocally connected with glutamatergic subthalamic nucleus (STN) neurons and this excitatory-inhibitory circuit is considered as the central pattern generator of the BG. As GP neurons excitability is under the control of their axon collaterals, alteration of lateral inhibition in the GP has been proposed to be a key factor in the emergence of correlated bursting activity in the GP-STN network. The main hypothesis that will be tested in this project is that the loss of dopamine in PD leads to abnormal lateral inhibition in the GP, which contribute in part to the emergence of pathological firing pattern. Therefore, the main objective is to study lateral inhibition in the GP and its regulation by dopamine by using electrophysiological recordings of GP neurons in rat brain slices combined to molecular biology and immunohistochemistry. The influence of dopamine will be assessed by comparing neuronal excitability and GABAergic synaptic transmission in absence and presence of dopamine receptor agonists and in normal and dopamine-depleted animals. There are 3 specific aims (SA) of this project: SA1:. We will characterize the impact of dopamine on neuronal excitability, the nature of the dopamine receptor(s) involved in this modulation and determine which ionic channels are the effectors of this modulation in these two population of neurons. SA2: We will study pallidal lateral inhibition by defining the properties of pallido-pallidal synapses, by determining their synaptic plasticity and the influence of dopamine on the release of GABA in the GP. We will also determine how GABAergic inhibition is integrated by GP neurons and how it affects their excitability. SA3: Finally, the alteration of lateral inhibition in dopamine-depleted animals will be studied. We will use the gold-standard model of PD, the unilateral 6-hydroxydopamine lesioned rats and we will look for changes of lateral inhibition and GABAA receptor subunit expression between intact and dopamine-depleted animals. With the present project, we expect to elucidate the GABAergic microcircuit in the GP, and its role in normal and pathological neuronal activity. This project will generate a comprehensive analysis of GABAergic regulation of this nucleus.