Synaptic plasticity may underlie l-DOPA induced dyskinesia

Abstract

l-DOPA provides highly effective treatment for Parkinson's disease, but l-DOPA induced dyskinesia (LID) is a very debilitating response that eventually is presented by a majority of patients. A central issue in understanding the basis of LID is whether it is due to a response to chronic l-DOPA over years of therapy, and/or due to synaptic changes that follow the loss of dopaminergic neurotransmission and then triggered by acute l-DOPA administration. We review recent work that suggests that specific synaptic changes in the D1 dopamine receptor-expressing direct pathway striatal projection neurons due to loss of dopamine in Parkinson's disease are responsible for LID. Chronic l-DOPA may nevertheless modulate LID through priming mechanisms.

Figure 1. Modulation of SPN neuronal plasticity occurs at multiple synaptic sites

A) Simplified schematic of striatofugal SPN and ascending DA projections in the rodent brain. DA neurons of the SNc can influence neuronal plasticity in distinct microcircuits via post- and presynaptic DA receptors in the striatum, GP and SNr. B) Immunolabel for tyrosine hydroxylase (TH) in mouse ventral midbrain showing DA neurons of the SNc and their dendritic processes extending into the SNr. Somatodendritically released DA presumably influences motor functions by local actions within the midbrain. Scale = 50 μm. C) Immunolabel for TH (green) and D1R (red) in a mouse midbrain section. D1R are preferentially located on the terminals of D1-SPNs, and thus DA neurons directly influence local GABA release from the striatonigral direct pathway. Scale = 100 μm. D) Labeling of D1-SPNs synapses with the fluorescent vesicular probe FM1–43 to study presynaptic plasticity produced by DA denervation. Upper panels show 2-photon images of FM1-43-labeled D1-SPN synaptic boutons in the SNr (left), and a time-series of destaining from a single fluorescent bouton during stimulation of D1-SPN projections (right). Loss of fluorescence represents the fusion of GABA-containing vesicles during electrically evoked synaptic activity and the rate of decay reveals the probability of neurotransmitter release. Bottom panel shows the normalized FM1-43 fluorescence as a function of time from >100 D1-SPN synaptic boutons in brain slice preparations from DA intact (sham) and denervated parkinsonian mice (6-OHDA). The rate of vesicular fusion is greatly increased in DA denervated animals, indicating that increased GABA release during synaptic activity provides a potential mechanism for LID. Scale = 3 μm.

Figure 2. Model of how DA neurons control motor actions by engaging the striatonigral direct pathway circuit via D1R in the striatum and SNr

In normal conditions, midbrain DA neurons display various firing rates with episodes of bursts and tonic activity interspersed with pauses. Subsequent changes in extracellular DA will engage different subsets of D1-SPNs in the striatum. D1Rs located in the SNr can directly filter D1-SPN GABA output to provide for action selection, represented here as inhibition of different SNr projection neurons. In PD, DA neurons degenerate and homeostatic plasticity develops which leads to increased intrinsic excitability and evoked GABA release from D1-SPN synapses in response DA replacement with L-DOPA. Increased output from D1-SPNs and loss of filtering by presynaptic receptors, for instance by GABA_B receptors (not shown), will result in surges of GABA efflux in the SNr. The lack of selection of GABA output from D1-SPNs will trigger hyperkinetic responses when extracellular DA is produced by L-DOPA administration, such as LID.

Figure 3. Presynaptic signaling mechanisms in D1-SPNs that may be involved in synaptic plasticity triggered by disrupted D1R signaling in PD

Activation of D1Rs triggers a series of downstream signal transduction pathways, principally driven by the control of the cAMP/PKA/DARPP-32 cascade. Direct control of presynaptic activity by somatodendritic DA release is achieved by regulation of voltage-dependent potassium and calcium channels that together control the probability of GABA release. GABA_B receptor activity, which inhibits D1R driven activation of cAMP, is lost in DA denervated animals [30], presumably resulting from compensatory changes in D1R mediated signal transduction. Long-term changes in synaptic function may also involve the regulation of synapsins, a group of phosphoproteins that control the recruitment of synaptic vesicles from the resting pool. Compensatory mechanisms may result in homeostatic plasticity that attempt to overcome the loss of DA and sustain normal synaptic function in prodromal PD. As neurodegeneration progresses, however, the homeostatic plasticity eventually can trigger LID.