Elsevier

Biological Psychiatry

Volume 75, Issue 9, 1 May 2014, Pages 711-722
Biological Psychiatry

Archival Report
L-DOPA Treatment Selectively Restores Spine Density in Dopamine Receptor D2–Expressing Projection Neurons in Dyskinetic Mice

https://doi.org/10.1016/j.biopsych.2013.05.006Get rights and content

Background

L-3,4-dihydroxyphenylalanine (L-DOPA)–induced dyskinesia is an incapacitating complication of L-DOPA therapy that affects most patients with Parkinson’s disease. Previous work indicating that molecular sensitization to dopamine receptor D1 (D1R) stimulation is involved in dyskinesias prompted us to perform electrophysiological recordings of striatal projection “medium spiny neurons” (MSN). Moreover, because enhanced D1R signaling in drug abuse induces changes in spine density in striatum, we investigated whether the dyskinesia is related to morphological changes in MSNs.

Methods

Wild-type and bacterial artificial chromosome transgenic mice (D1R-tomato and D2R–green fluorescent protein) mice were lesioned with 6-hydroxydopamine and subsequently treated with L-DOPA to induce dyskinesia. Functional, molecular, and structural changes were assessed in corticostriatal slices. Individual MSNs injected with Lucifer-Yellow were detected by immunohistochemistry for three-dimensional reconstructions with Neurolucida software. Intracellular current-clamp recordings with high-resistance micropipettes were used to characterize electrophysiological parameters.

Results

Both D1R-MSNs and D2R-MSNs showed diminished spine density in totally denervated striatal regions in parkinsonian mice. Chronic L-DOPA treatment, which induced dyskinesia and aberrant FosB expression, restored spine density in D2R-MSNs but not in D1R-MSNs. In basal conditions, MSNs are more excitable in parkinsonian than in sham mice, and excitability decreases toward normal values after L-DOPA treatment. Despite this normalization of basal excitability, in dyskinetic mice, the selective D1R agonist SKF38393 increased the number of evoked action potentials in MSNs, compared with sham animals.

Conclusions

Chronic L-DOPA induces abnormal spine re-growth exclusively in D2R-MSNs and robust supersensitization to D1R-activated excitability in denervated striatal MSNs. These changes might constitute the anatomical and electrophysiological substrates of dyskinesia.

Section snippets

Methods and Materials

This study was carried out in 3–4-month-old male C57BL6 wild-type (WT) and bacterial artificial chromosome (BAC)-transgenic mice (D1R-tomato or D2R–enhanced green fluorescent protein [eGFP]). Animals were housed and maintained following the guidelines from European Union Council Directive (86/609/European Economic Community). Mice received an intrastriatal 6-OHDA (Sigma-Aldrich, Madrid, Spain) injection (parkinsonian group) or vehicle (sham group), as described previously (26). The mice

Induction of Dyskinesias in 6-OHDA-Lesioned Mice

To quantify L-DOPA-induced dyskinesias in parkinsonian WT, D1R-tomato, or D2R-eGFP mice, we scored orofacial, limb, and locomotive dyskinesia 30 min after L-DOPA or saline injection as previously described 14, 16, 26. After L-DOPA, parkinsonian BAC-transgenic mice developed marked dyskinetic movements affecting the contralateral forelimb and orofacial structures, together with trunk dystonia, similar to those observed in WT mice (Figure 1A). These symptoms were not observed in the saline group.

Discussion

Here we show that 6-OHDA lesions in the striatum reduce spine density in D1R-positive and D2R-positive MSN of D1R-tomato and D2R-eGFP BAC-transgenic mice. This reduction was similar to that observed in unidentified MSN in WT C57BL6 mice. We further show that these changes are restricted to totally denervated striatal areas. A major finding of the present study is that chronic L-DOPA, at doses inducing dyskinesia, reverses dendritic spine loss selectively in striatal MSNs expressing the D2R.

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