L-DOPA treatment selectively restores spine density in D2R-expressing projection neurons in dyskinetic mice

SUÁREZ LM; SOLIS O; CARAMÉS JM; TARAVINI IR; SOLIS JM; MURER MG; MORATALLA R

San Diego, California

Congreso; 2013 Annual meeting of the Society for Neuroscience; 2013

Society for Neuroscience

L-DOPA-induced dyskinesia is an incapacitating complication of L-DOPA therapy which affects most patients with Parkinson?s disease. Previous work indicating that molecular sensitization to D1 dopamine receptor (D1R) stimulation is involved in dyskinesias prompted us to perform electrophysiological recordings of striatal projection ?medium spiny neurons? (MSN) and to see whether dyskinesia is related to morphological changes in striatal projection neurons. Lesioned, wild type and BAC transgenic mice (D1R-tomato and D2R-GFP) mice were treated with L-DOPA to induce dyskinesia. Functional, molecular and structural changes were assessed in corticostriatal slices. Individual identified MSNs were injected with Lucifer-Yellow for 3-D reconstructions with Neurolucida software. Intracellular current-clamp recordings were used to characterize electrophysiological parameters. Our results indicated that both D1R- 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, selectively restored spine density in D2R-MSNs but not in D1R-MSNs. In basal conditions, MSN are more excitable in parkinsonian than in sham mice, and excitability decreases towards normal values following 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 to 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.