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

Authors
Suárez, Luz M.; Solís, Oscar; Carames, José M.; Taravini, Irene Rita Eloisa; Solis, José M.; Murer, Mario Gustavo; Moratalla, Rosario
Publication Year
2014
Language
English
Format
article
Status
Published version
Description
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 D1RMSNs. 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 D1Ractivated excitability in denervated striatal MSNs. These changes might constitute the anatomical and electrophysiological substrates of dyskinesia.
Fil: Suárez, Luz M.. Consejo Superior de Investigaciones Cientificas; España. Universidad Carlos III de Madrid. Instituto de Salud; España
Fil: Solís, Oscar. Consejo Superior de Investigaciones Cientificas; España. Universidad Carlos III de Madrid. Instituto de Salud; España
Fil: Carames, José M.. Consejo Superior de Investigaciones Cientificas; España. Universidad Carlos III de Madrid. Instituto de Salud; España
Fil: Taravini, Irene Rita Eloisa. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones Farmacológicas; Argentina
Fil: Solis, José M.. Consejo Superior de Investigaciones Cientificas; España
Fil: Murer, Mario Gustavo. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Ciencias Fisiológicas. Laboratorio de Fisiología de Circuitos Neuronales; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Moratalla, Rosario. Consejo Superior de Investigaciones Cientificas; España. Universidad Carlos III de Madrid. Instituto de Salud; España
Subject
BEHAVIORAL SENSITIZATION
DYSKINESIA
L-DOPA
MEDIUM SPINY NEURON
Parkinson's disease
STRIATUM
THREE-DIMENSIONAL NEURONAL RECONSTRUCTION
Neurociencias
Medicina Básica
CIENCIAS MÉDICAS Y DE LA SALUD
Access level
Restricted access
License
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
Repository
CONICET Digital (CONICET)
Institution
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identifier
oai:ri.conicet.gov.ar:11336/15779