A basis for the pathological oscillations in basal ganglia: the crucial role of dopamine.

Parkinson’s disease is a progressive neurodegenerative movement disorder characterized by poverty and slowness of movement (akinesia and bradykinesia), muscle rigidity and tremor. The core pathology of the disease is the degeneration of midbrain dopaminergic neurons in the substantia nigra pars compacta that project to the striatum and other basal ganglia nuclei. The striatum is the main input structure of the basal ganglia and receives excitatory projections from many cortical areas and thalamic nuclei. The output neurons of the striatum, named medium spiny neurons, are GABAergic and project to both the globus pallidus internus and externus, and to substantia nigra pars reticulata which are also GABAergic. The other nucleus within the basal ganglia is the subthalamic nucleus which receives direct cortical inputs as well as an input from the globus pallidus externus and its glutamatergic neurons project to the globus pallidus internus and substanatia nigra pars reticulata (see Figure 1). Figure 1 Simplified diagram of basal ganglia connections. Excitatory and inhibitory connections are distinguished by black and gray lines respectively. The overall direct effect of dopamine on synaptic transmission in each nucleus is indicated by the (+) and (−) . Until recently it was thought that the loss of dopaminergic inputs to the striatum led to hyperactivity of the globus pallidus internus and substanatia nigra pars reticulata, and this caused hypokinetic motor symptoms. This model, frequently termed the “rate” model, provided a very plausible explanation for the bradykinesia and akinesia that develops in Parkinson’s disease, since the proposed hyperactivity of the GABAergic output nuclei, globus pallidus internus and substanatia nigra pars reticulata would lead to hypoactivity in the thalamic relay to motor cortex thus leading to a decreased cortical excitability and slowness and poverty of movements. Initial experimental evidence provided support for this model and was the basis for introduction of pallidotomies and deep brain stimulation in the subthalamic nucleus and globus pallidus internus for treating Parkinson’s disease. However, recent findings have cast doubt on the validity of this model and prompted a re-examination of the mechanisms underlying the symptoms of Parkinson’s disease [1]. In particular, electrophysiological recordings in cortico-basal ganglia circuits in animal models and Parkinson’s disease patients revealed that chronic dopamine depletion is associated with alterations in firing patterns and oscillatory activity and it is now widely believed that these changes play a more important role in mediating the pathophysiology than changes in firing rates. Many of these advances were facilitated by the opportunity afforded by the therapeutic procedure of implantation of deep brain stimulation electrodes in the subthalamic nucleus and globus pallidus internus which permitted the recordings of neuronal acitivity and local field potentials in Parkinson’s disease patients. Also the use of animal models of Parkinson’s disease, in particular monkeys treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and rats treated with 6-hydroxydopamine, chemicals leading to substantia nigra pars compacta cell death has permitted investigation of the effects of DA depletion on basal ganglia function. There is growing evidence that increased synchrony between neurons and increased oscillatory firing within the basal ganglia play a key role in the pathophysiology of Parkinson’s disease. The origin of these pathological activities, however, is still under extensive investigation and is reviewed below.