title: L-DOPA treatment selectively restores spine density in dopamine receptor D2-expressing projection neurons in dyskinetic mice.
abstract: 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.
authors.affiliation: Instituto Cajal, Consejo Superior de Investigaciones Científicas, CSIC, Madrid Spain; CIBERNED, Instituto de Salud Carlos III, Madrid Spain.
authors.forename: Luz M
authors.initials: LM
authors.lastname: Suárez
authors.affiliation: Instituto Cajal, Consejo Superior de Investigaciones Científicas, CSIC, Madrid Spain; CIBERNED, Instituto de Salud Carlos III, Madrid Spain.
authors.forename: Oscar
authors.initials: O
authors.lastname: Solís
authors.affiliation: Instituto Cajal, Consejo Superior de Investigaciones Científicas, CSIC, Madrid Spain; CIBERNED, Instituto de Salud Carlos III, Madrid Spain.
authors.forename: Jose M
authors.initials: JM
authors.lastname: Caramés
authors.affiliation: Instituto de Investigaciones Farmacológicas, Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina.
authors.forename: Irene R
authors.initials: IR
authors.lastname: Taravini
authors.affiliation: Hospital Universitario Ramón y Cajal, IRYCIS, Madrid Spain.
authors.forename: Jose M
authors.initials: JM
authors.lastname: Solís
authors.affiliation: Departamento de Fisiología y Biofísica, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina.
authors.forename: Mario G
authors.initials: MG
authors.lastname: Murer
authors.affiliation: Instituto Cajal, Consejo Superior de Investigaciones Científicas, CSIC, Madrid Spain; CIBERNED, Instituto de Salud Carlos III, Madrid Spain. Electronic address: moratalla@cajal.csic.es.
authors.forename: Rosario
authors.initials: R
authors.lastname: Moratalla
mesh_terms: D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000494:pharmacology; D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects* / Q000627:therapeutic use; D002540:Cerebral Cortex / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D003342:Corpus Striatum / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D049229:Dendritic Spines / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D018491:Dopamine Agonists / Q000494:pharmacology; D004409:Dyskinesia, Drug-Induced / Q000473:pathology* / Q000503:physiopathology; D007980:Levodopa / Q000009:adverse effects* / Q000627:therapeutic use; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D016627:Oxidopamine; D020734:Parkinsonian Disorders / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D017447:Receptors, Dopamine D1 / Q000819:agonists / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism
chemical_list: D000978:Antiparkinson Agents; D018491:Dopamine Agonists; C483819:Fosb protein, mouse; D016760:Proto-Oncogene Proteins c-fos; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D007980:Levodopa; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; D016627:Oxidopamine
keywords: Behavioral sensitization; L-DOPA; Parkinson’s disease; dyskinesia; medium spiny neuron; striatum; three-dimensional neuronal reconstruction