Functional organization of the basal ganglia: therapeutic implications for Parkinson's disease.

The basal ganglia (BG) are a highly organized network, where different parts are activated for specific functions and circumstances. The BG are involved in movement control, as well as associative learning, planning, working memory, and emotion. We concentrate on the "motor circuit" because it is the best understood anatomically and physiologically, and because Parkinson's disease is mainly thought to be a movement disorder. Normal function of the BG requires fine tuning of neuronal excitability within each nucleus to determine the exact degree of movement facilitation or inhibition at any given moment. This is mediated by the complex organization of the striatum, where the excitability of medium spiny neurons is controlled by several pre- and postsynaptic mechanisms as well as interneuron activity, and secured by several recurrent or internal BG circuits. The motor circuit of the BG has two entry points, the striatum and the subthalamic nucleus (STN), and an output, the globus pallidus pars interna (GPi), which connects to the cortex via the motor thalamus. Neuronal afferents coding for a given movement or task project to the BG by two different systems: (1) Direct disynaptic projections to the GPi via the striatum and STN. (2) Indirect trisynaptic projections to the GPi via the globus pallidus pars externa (GPe). Corticostriatal afferents primarily act to inhibit medium spiny neurons in the "indirect circuit" and facilitate neurons in the "direct circuit." The GPe is in a pivotal position to regulate the motor output of the BG. Dopamine finely tunes striatal input as well as neuronal striatal activity, and modulates GPe, GPi, and STN activity. Dopaminergic depletion in Parkinson's disease disrupts the corticostriatal balance leading to increased activity the indirect circuit and reduced activity in the direct circuit. The precise chain of events leading to increased STN activity is not completely understood, but impaired dopaminergic regulation of the GPe, GPi, and STN may be involved. The parkinsonian state is characterized by disruption of the internal balance of the BG leading to hyperactivity in the two main entry points of the network (striatum and STN) and excessive inhibitory output from the GPi. Replacement therapy with standard levodopa creates a further imbalance, producing an abnormal pattern of neuronal discharge and synchronization of neuronal firing that sustain the "off" and "on with dyskinesia" states. The effect of levodopa is robust but short-lasting and converts the parkinsonian BG into a highly unstable system, where pharmacological and compensatory effects act in opposing directions. This creates a scenario that substantially departs from the normal physiological state of the BG.