From the Research
Parkinson's disease involves dysfunction in the direct and indirect pathways of the basal ganglia, which normally work together to control movement, with the most recent evidence suggesting that dopamine-mediated plasticity preserves excitatory connections to direct pathway striatal projection neurons and motor function in a mouse model of Parkinson's disease 1.
Pathways in Parkinson's Disease
The direct pathway, where dopamine from the substantia nigra activates D1 receptors on striatal neurons, ultimately reduces inhibition of the thalamus and facilitates movement.
- The indirect pathway involves dopamine activating D2 receptors, which normally suppresses this pathway to prevent excessive movement inhibition.
- In Parkinson's disease, the loss of dopaminergic neurons in the substantia nigra disrupts this balance, leading to an underactive direct pathway and an overactive indirect pathway.
Impact on Motor Function
With reduced dopamine, the direct pathway becomes underactive, failing to facilitate intended movements, while the indirect pathway becomes overactive, excessively suppressing movement.
- This imbalance produces the cardinal symptoms of Parkinson's disease: bradykinesia (slowness of movement), rigidity, and resting tremor.
- Treatment with levodopa or dopamine agonists aims to restore this balance by increasing dopamine signaling, thereby enhancing direct pathway activity while suppressing the overactive indirect pathway, as supported by a comparative effectiveness study of dopamine agonists and monoamine oxidase type-B inhibitors for Parkinson's disease 2.
Recent Findings
Recent studies have also highlighted the role of inhibition of indirect pathway activity in causing abnormal decision-making in a mouse model of impulse control disorder in Parkinson's disease 3, and the loss of homeostasis in the direct pathway in a mouse model of asymptomatic Parkinson's disease 4.
- Additionally, functional segregation of basal ganglia pathways in Parkinson's disease has been investigated, revealing that the hyperdirect and indirect pathways are differentially involved in cognitive aspects of cautious motor preparation and kinematic gain control during motor performance 5.