L-DOPA treatment selectively restores spine density in D2Rexpressing projection neurons in dyskinetic mice

SUAREZ LUZ; SOLIS O; CARAMES J.M.; TARAVINI IRE; SOLIS JM; MURER MG; MORATALLA R

BIOLOGICAL PSYCHIATRY

ELSEVIER SCIENCE INC

Lugar: Amsterdam; Año: 2014 vol. 75 p. 711 - 722

0006-3223

Background: L-DOPA-induced dyskinesia is an incapacitating complicationof L-DOPA therapy which affects most patients with Parkinson´s disease.Previous work indicating that molecular sensitization to D1 dopaminereceptor (D1R) stimulation is involved in dyskinesias prompted us toperform electrophysiological recordings of striatal projection "mediumspiny neurons" (MSN). Moreover, because enhanced D1R signaling in drugabuse induces changes in spine density in striatum, we investigatedwhether the dyskinesia is related to morphological changes in MSNs.Methods: Wild type and BAC transgenic mice (D1R-tomato and D2R-GFP) micewere lesioned with 6-hydroxydopamine and subsequently treated with L-DOPAto induce dyskinesia. Functional, molecular and structural changes wereassessed in corticostriatal slices. Individual MSNs injected withLucifer-Yellow were used for DAB-derived 3-D reconstructions withNeurolucida software. Intracellular current-clamp recordings with highresistancemicropipettes were used to characterize electrophysiologicalparameters.Results: Both D1R-MSNs and D2R-MSNs showed diminished spine density intotally denervated striatal regions in parkinsonian mice. Chronic L-DOPAtreatment, which induced dyskinesia and aberrant FosB expression,restored spine density in D2R-MSNs but not in D1R-MSNs. In basalconditions, MSN are more excitable in parkinsonian than in sham mice, andexcitability decreases towards normal values following L-DOPA treatment.Despite this normalization of basal excitability, in dyskinetic mice, theselective D1R agonist SKF38393 increased the number of evoked actionpotentials in MSNs, compared to sham animals.Conclusions: Chronic L-DOPA induces abnormal spine re-growth exclusivelyin D2R-MSNs and robust supersensitization to D1R-activated excitabilityin denervated striatal MSNs. These changes might constitute theanatomical and electrophysiological substrates of dyskinesia.