Targeting the cholinergic system in Parkinson’s disease

摘要

Diagrams of the striatal motor control system in health and pathology. a Schematic showing the organizing principle of the motor control system in the brain. The activities of the direct and indirect pathways in the striatum are indicated by orange and blue ovals, respectively. Dopamine neurons (green) from the midbrain and striatal ChIs (purple) are also shown. In the healthy brain, action sequences are encoded in the cortex and thalamus, transferred to the striatum (gray arrow), and initiated immediately after a brief dopamine transient and acetylcholine release. Once the movement kicks off, the actions (movement icons) are sequentially performed in a dopamine-independent manner. A highly coordinated interplay of striatal circuitry governs the execution of action sequences, with the direct pathway (orange) facilitating the performance of the appropriate actions and the indirect pathway (blue) suppressing unwanted ones. The precise balance of activity between the two pathways is essential for the accurate performance of motion sequences (indicated by the merged area with similar brightness of each color). Once the movement is finished, the consequence of the motion is evaluated, and a feedback signal of prediction error is generated in both ChIs and dopamine neurons for Hebbian modification of the striatal circuitry. If the circuits involved in the motion generate positive consequences for survival, they are enhanced (through the formation of synaptic LTP) to make them easier to recruit in the future. In the opposite scenario, if the behavioral consequences are worse than expected, the responsible circuit will be undermined (through the formation of synaptic LTD) and will be harder to activate thereafter. This functional feedback loop underlies the basis of motor learning in the striatum, where ChIs and dopamine neurons play essential roles in both the action initiation and result evaluation phases. b In parkinsonian conditions, dopamine neurons are lost. Falling dopamine levels in the striatum generate aberrant homeostatic adaptations in striatal neurons and synaptic plasticity in the striatal circuitry. ChIs become hyperactive and fire more synchronously. MSNs undergo homeostatic changes trying to restore the balance over time. The intrinsic excitability of MSNs of the direct pathway increased due to long-term loss of D1 activation, and the excitability of MSNs of the indirect pathway decreased due to loss of D2 activation. The bidirectional synaptic plasticity at cortical striatal synapses is the key cellular basis for motor learning and movement control. Nevertheless, since there is not enough dopamine left in PD, no LTP can form in the direct pathway while no LTD can form in the indirect pathway; this aberrantly suppresses the direct pathway (illustrated as the lighter orange oval) but artificially reinforces the indirect pathway (illustrated as the darker blue oval). Hence, movement commands prefer to flow through the indirect pathway but not through the direct pathway, generating an enhanced “stop” signal and a diminished “go” signal (dashed arrows). Without dopamine, feedback on behavioral consequences is not generated, and no proper motor learning occurs in the striatum. c When PD patients are treated with levodopa, the striatal circuitry is constantly bombarded by abnormally sustained dopamine stimulation. Although levodopa administration can restore LTP and LTD formation in striatal synapses, it fails to replicate the spatiotemporal pattern of dopamine signaling in the healthy brain. As a result, synaptic strength is no longer governed by the outcomes of behaviors but is erratically regulated. Since higher dopamine levels prefer to strengthen the direct pathway (illustrated as the darker orange oval) but suppress the indirect pathway (illustrated as the lighter blue oval), unwanted actions are not sufficiently suppressed by the indirect pathway, causing random execution of movement (arrows and movement icons). Reduced ChI activity and cholinergic transmission have been reported after long-term levodopa treatment but contradicting evidence exists suggesting that ChIs might still be hyperactive