Functional Connectivity of the Basal Ganglia Circuitry: Cellular and Synaptic Mechanisms

The basal ganglia are interconnected subcortical nuclei, and constitute part of the essential cortico-subcortical re-entrant loops that also involve the thalamus and the cortex. Neural circuits involving the basal ganglia are related to many important motor and cognitive functions, the impairment of which may result in different clinical disease such as Parkinson’s disease (PD), a very common neurodegenerative condition. The striatum is the gateway of externalnetwork to the basal ganglia and is the major target of dopamine, the deficit of which is presumed as the primary cause of PD. However, the classical model of dopamine action on striatum has been challenged by recent electrophysiological characterizations. For example, application of dopamine to a resting neuron actually does nothing obvious in the striatum. On the other hand, one of the most salient abnormalities in PD has been the pathological oscillations in the pallido-subthalamic (GPe-STN) network. The oscillation seems to assume an important role in the pathophysiology of PD, as deep brain stimulation on STN has become an established treatment of PD-related symptoms in neurological clinics. We therefore propose to study the intrinsic and synaptic mechanisms underlying the operation of the basal ganglia circuitry, focusing on the cortico-striatal and the pallido-subthalamic pathways. We will first clarify the contribution of different ionic conductances to, and the effect of their gating properties on, membrane excitability and firing patterns of the striatal (MSN) and STN neurons by whole-cell patch clamp recordings. We will then explore the synaptic mechanisms contributing to the network activity in the cortico-striatal and the pallido-subthalamic connections in brain slices, including the interplay among the intrinsic membrane properties, excitatory as well as inhibitory synaptic inputs, and the activity-dependent bidirectional modulation of synaptic transmission. Because of stable hyperpolarizing resting membrane potential in MSNs, the coherence of excitatory synaptic inputs for the generation of spikes will be especially noted in the cortico-striatal pathway. In the pallido-subthalamic pathway, spatiotemporal patterns of synaptic inputs also in theory affect generation of rhythmic bursting. We surmise that the rhythmic bursts provide enough inhibitory input signals to the thalamus and the cortex, which in turn affect motor function in PD. In addition, D1 and D2 dopamine receptor- and cholinergic receptor-mediated modulation of the network activity in the basal ganglia circuits will be studied. Therefore, these studies will not only enhance our understanding of the contributions of neuromodulators and intrinsic as well as synaptic mechanisms to information processing in the basal ganglia circuitry, but also shed light on the selection and shaping of an appropriate motor command from or related output to the cerebral cortex.

Project ID:PA10001-0717
External Project ID:NSC99-2311-B182-001-MY3