Aberrant striatal plasticity is specifically associated with dyskinesia following levodopa treatment

Abstract

Chronic levodopa treatment for Parkinson's disease often results in the development of abnormal involuntary movement, known as L-dopa-induced dyskinesia (LIDs). Studies suggest that LIDs may be associated with aberrant corticostriatal plasticity. Using in vivo extracellular recordings from identified Type I and Type II medium spiny striatal neurons, chronic L-dopa treatment was found to produce abnormal corticostriatal information processing. Specifically, after chronic L-dopa treatment in dopamine-depleted rats, there was a transition from a cortically evoked long-term depression (LTD) to a complementary but opposing form of plasticity, long-term potentiation, in Type II "indirect" pathway neurons. In contrast, LTD could still be induced in Type I neurons. Interestingly, the one parameter that correlated best with dyskinesias was the inability to de-depress established LTD in Type I medium spiny striatal neurons. Taken as a whole, we propose that the induction of LIDs is due, at least in part, to an aberrant induction of plasticity within the Type II indirect pathway neurons combined with an inability to de-depress established plastic responses in Type I neurons. Such information is critical for understanding the cellular mechanisms underlying one of the major caveats to L-dopa therapy.

Figure 1

Behavioral testing for the expression of L-DOPA induced dyskinesia. Dyskinetic rats demonstrated an increase in axial (A), limb (B) and orolingual (C) AIMS over treatment days and a contralateral limb asymmetry bias compared to non-dyskinetic rats (D). * represents significant difference between dyskinetic and non-dyskinetic rats (p<0.05; 2-way ANOVA: Holm-Sidak post-hoc: n = 24–27 rats/group).

Figure 2

Characterization of striatonigral and striatopallidal neurons by antidromic activation from substantia nigra pars reticulata. A representative example of the response to paired pulse stimulation in a SNR-projecting, type I (A) and non-SNr projecting, type II neuron (D). Twenty overlaid consecutive traces are shown with the numbers in brackets demonstrating the number of evoked spikes for the first and second cortical stimuli (A and D). The spike probability for the type I neuron was 0.65 for the first stimulation and 0.25 for the second (A) whereas the spike probability of the type II neurons was 0.25 for the first and 0.9 for the second stimulation. Electrical activation of the SNr induces a reliable antidromic action potential in type I (but not type II) neurons (B and E). Furthermore the action potential induced by SNr stimulation was confirmed to be antidromic by collision with a cortical evoked spike (C).

Figure 3

Characterization of type I and II medium spiny neurons by juxtacellular labeling and retrograde labeling from the external globus pallidus. Representative photomicrographs of juxtacellularly labeled neurons (red) and GP retrogradely labeled neurons (green) throughout the CPU. Type I neurons identified by paired pulse cortical stimulation (D) do not reliably innervate the GP (A–C). In contrast, type II neurons primarily comprise the indirect, striato-pallidal neurons (F–H). E and F demonstrate reliable entrainment of the medium spiny neuron to the depolarizing current pulses.

Figure 4

6-OHDA lesions block the HFS-evoked LTD in striatopallidal but not in striatonigral neurons. HFS (open circles) induces a decrease of the cortical-evoked activity in both striatonigral (A) and striatopallidal (B) neurons in intact animals (left panels). LFS (open squares) produces a return to the baseline in striatonigral but not in striatopallidal neurons of intact rats (left panels). 6-OHDA lesions (right panels) prevent HFS-evoked LTD in striatopallidal neurons, while the response in striatonigral neurons remains intact. LFS further augments the LTD induced by HFS in striatonigral neurons, but has no significant effect on type II neurons. Inserts represent the average spike probability (mean ± SEM) in baseline (black), after HFS (dark grey) and after LFS (light grey). * represents significant difference between groups (p<0.05; 1-way ANOVA: Holm-Sidak post-hoc: n = 6–8 neurons/group).

Figure 5

Chronic L-DOPA treatment enables HFS-evoked LTP in both dyskinetic and non-dyskinetic rats in striatopallidal neurons, but its reversal with LFS is selectively altered in dyskinetic rats. Striatonigral neurons (top panels) exhibit LTD after HFS in both non-dyskinetic (left) and dyskinetic (right) rats (open circles). In contrast, striatopallidal neurons (bottom) display a significant LTP in both dyskinetic (left) and non dyskinetic (right) rats after HFS (open circles). A reversal of LTD induced by LFS is observed in striatopallidal neurons only in the dyskinetic rats. These data suggest that the LTP is more labile in dyskinetic rats following chronic L-DOPA treatment. Inserts represent the average spike probability (mean ± SEM) in baseline (black), after HFS (dark grey) and after LFS (light grey). * represents significant difference between groups (p<0.05; 1-way ANOVA: Holm-Sidak post-hoc: n = 6–8 neurons/group).