Basal Ganglia Circuitry and Synaptic Connectivity

Abstract

The basal ganglia are several synaptically interconnected subcortical structures that play important roles in regulating various aspects of psychomotor behaviors, and are central to the pathophysiol-ogy of common human movement disorders such as Parkinson's and Huntington's diseases (PD/HD). These structures classically include: 1) the striatum, which comprises the caudate nucleus (CD), puta-men (PUT), and nucleus accumbens (Acc); 2) the globus pallidus, which includes the external (GPe; globus pallidus in nonprimates) and internal (GPi; entopeduncular nucleus [EPN] in nonprimates) segments; 3) the subthalamic nucleus (STN); and 4) the substantia nigra, which comprises the pars compacta (SNc) and pars reticulata (SNr) (Fig. 1). The striatum, and to a lesser extent, the STN are the major receptive components of the basal gan-glia. They both receive excitatory glutamatergic projections from the cerebral cortex and the thalamus. They also receive modulatory dopaminergic inputs from the SNc and ventral tegmental area (VTA) as well as serotonergic inputs from the dorsal raphe nucleus (DR). The striatum projects directly, and indirectly via the GPe and STN, to the output nuclei of the basal ganglia, the GPi, and SNr (1-3). The direct and indirect striatal projections as well as the GPe projection to the STN use the inhibitory amino acid, γ-aminobutyric acid (GABA), as neurotransmitter. In contrast, the pathways from the STN to the GPi and SNr are excitatory and glutamatergic (3). Thus, the basal ganglia output nuclei, GPi and SNr, receive opposite inhibitory and excitatory signals from the direct and indirect pathways. The GPi and SNr projections to the thalamus are GABAergic and tend to inhibit thalamocorti-cal feedback which, in turn, is excitatory and glutamatergic. Furthermore, the output neurons of the GPi and SNr project to specific brainstem structures that provide descending projections to motor nuclei in the medulla and spinal cord (Fig. 1). Therefore, the major circuitry of the basal ganglia is from the cortex, through its component structures, which then convey the information to the thala-mus and brainstem. The thalamus projects back upon frontal cortical areas whereas the brainstem sends feedback ascending projections to the basal ganglia or descending projections to medullary motor nuclei interconnected with the spinal cord (Fig.1). In addition to these main basal ganglia circuits, there are additional loops and connections that may play important roles in basal ganglia functions. These include projections from the GPe to the striatum, the substantia nigra, and the reticular thalamic nucleus; projections from the STN to the GPe, tegmental pedunculopontine nucleus (PPN), striatum, and SNc; and projections from the thalamus to the striatum, the pallidum, and the STN (3,4) (Fig. 1). In dealing with such a complex circuitry, and because of space limitations, this review will not cover every aspects of the basal ganglia connectivity, but will