L-DOPA Oppositely Regulates Synaptic Strength and Spine Morphology in D1 and D2 Striatal Projection Neurons in Dyskinesia.
Dopamine depletion in Parkinson's disease (PD) produces dendritic spine loss in striatal medium spiny neurons (MSNs) and increases their excitability. However, the synaptic changes that occur in MSNs in PD, in particular those induced by chronic L-3,4-dihydroxyphenylalanine (L-DOPA) treatment, are still poorly understood. We exposed BAC-transgenic D1-tomato and D2-eGFP mice to PD and dyskinesia model paradigms, enabling cell type-specific assessment of changes in synaptic physiology and morphology. The distinct fluorescence markers allowed us to identify D1 and D2 MSNs for analysis using intracellular sharp electrode recordings, electron microscopy, and 3D reconstructions with single-cell Lucifer Yellow injections. Dopamine depletion induced spine pruning in both types of MSNs, affecting mushroom and thin spines equally. Dopamine depletion also increased firing rate in both D1- and D2-MSNs, but reduced evoked-EPSP amplitude selectively in D2-MSNs. L-DOPA treatment that produced dyskinesia differentially affected synaptic properties in D1- and D2-MSNs. In D1-MSNs, spine density remained reduced but the remaining spines were enlarged, with bigger heads and larger postsynaptic densities. These morphological changes were accompanied by facilitation of action potential firing triggered by synaptic inputs. In contrast, although L-DOPA restored the number of spines in D2-MSNs, it resulted in shortened postsynaptic densities. These changes in D2-MSNs correlated with a decrease in synaptic transmission. Our findings indicate that L-DOPA-induced dyskinesia is associated with abnormal spine morphology, modified synaptic transmission, and altered EPSP-spike coupling, with distinct effects in D1- and D2-MSNs.
Instituto Cajal, Consejo Superior de Investigaciones Científicas, CSIC, 28002 Madrid, Spain.|CIBERNED, Instituto de Salud Carlos III, 28002 Madrid, Spain.
Luz M
LM
Suarez
Instituto Cajal, Consejo Superior de Investigaciones Científicas, CSIC, 28002 Madrid, Spain.|CIBERNED, Instituto de Salud Carlos III, 28002 Madrid, Spain.
Oscar
O
Solis
Instituto de Investigación en Discapacidades Neurológicas (IDINE), Dept. Ciencias Medicas, Facultad de Medicina, Universidad de Castilla-La Mancha, Campus Biosanitario, Albacete, Spain, Spain.
Carolina
C
Aguado
Instituto de Investigación en Discapacidades Neurológicas (IDINE), Dept. Ciencias Medicas, Facultad de Medicina, Universidad de Castilla-La Mancha, Campus Biosanitario, Albacete, Spain, Spain.
Rafael
R
Lujan
Instituto Cajal, Consejo Superior de Investigaciones Científicas, CSIC, 28002 Madrid, Spain.|CIBERNED, Instituto de Salud Carlos III, 28002 Madrid, Spain.
Rosario
R
Moratalla
D000818:Animals; D003342:Corpus Striatum / Q000473:pathology*; D004195:Disease Models, Animal; D004298:Dopamine / Q000494:pharmacology; D015259:Dopamine Agents / Q000009:adverse effects / Q000494:pharmacology; D004409:Dyskinesia, Drug-Induced / Q000209:etiology / Q000473:pathology*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005260:Female; D007980:Levodopa / Q000009:adverse effects / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects* / Q000648:ultrastructure; D016627:Oxidopamine / Q000633:toxicity; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000188:drug therapy; D017447:Receptors, Dopamine D1 / Q000235:genetics / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000235:genetics / Q000378:metabolism*; D013131:Spine / Q000473:pathology* / Q000648:ultrastructure; D013565:Sympatholytics / Q000633:toxicity
D015259:Dopamine Agents; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D013565:Sympatholytics; D007980:Levodopa; D016627:Oxidopamine; D004298:Dopamine
L-DOPA-induced dyskinesia; Parkinson's disease; medium-spiny-neurons; neuronal excitability; striatum