Pathophysiology

Parkinson’s disease involves the loss of dopaminergic neurons in the pars compacta region of the substantia nigra. These neurons project to the striatum, which integrates signals from the motor cortex and regulates neural circuits within the basal ganglia to control movement. Dopamine depletion results in an inhibition of the direct pathway and excitation of the indirect pathway leading to a hypokinetic disorder characterized by inhibition of movement (Kreitzer and Malenka, 2008).

Dopaminergic pathways in the normal (left) and PD (right) brain.

• The direct pathway initiates voluntary movement. It originates from nigrostriatal neurons which receive excitatory glutamatergic signals from the sensory motor cortex and thalamus. These neurons project to GABAergic neurons in the globus pallidus (GPi) and the substantia nigra pars reticulata (SNr), which then connect to the motor nuclei of the thalamus. Activation of the direct pathway results in disinhibition of the excitatory thalamocortical projections and facilitation of movement. Dopaminergic loss observed in PD decreases output of the direct pathway, potentiating the inhibition of the excitatory neurons that initiate movement (Kreitzer et al., 2008).

• The indirect pathway inhibits movement. This pathway originates from striatopallidal neurons that connect to GABAergic pallidal neurons, which project to glutamatergic neurons in the subthalamic nucleus (STN). These neurons project to the globus pallidus (GPi) and the substantia nigra pars reticulata (SNr), which then connect to the motor nuclei of the thalamus. This pathway inhibits thalamocortical neurons reducing movement. Dopaminergic loss observed in PD enhances output of the indirect pathway, leading to an increase in inhibitory stimulation and the resulting prominent bradykinetic symptoms (Kreitzer et al., 2008).