Project Details
Projekt
Consequences of HCN/h pacemarker channel deficency for cortico-basal ganglia circuit function
Applicant
Professor Dr. Dirk Isbrandt
Subject Area
Clinical Neurology; Neurosurgery and Neuroradiology
Term
from 2014 to 2019
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 101434521
Parkinson¿s disease (PD) is a common, debilitating neurodegenerative disorder characterized by profound circuit dysfunction in basal ganglia nuclei. The motor disability is specifically associated with the emergence of exaggerated beta (11-30 Hz) oscillations and synchronous, rhythmic spiking of neurons in basal ganglia. Abnormal beta oscillations develop after chronic dopamine depletion, are largely coherent in cortex and basal ganglia nuclei, and may be normalized by dopamine replacement therapies. Aberrant basal ganglia beta oscillations likely reflect synchronized rhythmic neuronal activities generated by local microcircuits, which become pathologically amplified within basal ganglia-cortical loops. However, the specific molecular and circuit mechanisms of this synchronization are not well understood. A crucial element of all basal ganglia microcircuits are pacemaker neurons, which are thought to be necessary for the generation of the normal rhythmic local and network activity sustaining motor function. These neurons can generate intrinsic membrane potential oscillations that strongly bias the timing of their action potential output. Pacemakers in the basal ganglia are very diverse. They range from the slow-spiking dopamine neurons in the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) to the fast-spiking (over 20 Hz) GABAergic substantia nigra pars reticulata (SNr) neurons and the cholinergic striatal interneurons (tonically active neurons or TANs.) Each of these cells expresses HCN channels, which produce the hyperpolarization-activated Ih-current. Ih can cause membrane resonance, an intrinsic biophysical property supporting pacemaker spiking. Altered Ih amplitude or HCN subunit expression is seen in many neurological disease states and disease models. To better understand basal ganglia pacemaker neurons at the cellular level, and their integration at the network and behavioral levels, we will alter their intrinsic membrane properties by genetic suppression of HCN/h channel activity. We hypothesize that a loss of function of HCN/h channels will specifically alter the pacemaker properties of these neurons and, in changing their firing patterns, alter synaptic and network activities, thus affecting both cognitive and motor function. We will use a combination of conditional expression of a dominant-negative HCN subunit, in vitro and in vivo electrophysiology, and behavioral analyses to characterize the consequences of attenuated HCN/h currents. We will record unit and network activity in key basal ganglia nuclei such as the dorsal striatum, the external segment of the globus pallidus (GPe), the subthalamic nucleus (STN), and the VTA/SN in both acute and awake-behaving preparations. In addition, we will investigate whether and how altered firing patterns and consequently the metabolic load of SNc neurons influence the vulnerability of these neurons in chronic PD models.
DFG Programme
Clinical Research Units
