title: Region-specific restoration of striatal synaptic plasticity by dopamine grafts in experimental parkinsonism.
abstract: Intrastriatal transplantation of dopaminergic neurons can restore striatal dopamine levels and improve parkinsonian deficits, but the mechanisms underlying these effects are poorly understood. Here, we show that transplants of dopamine neurons partially restore activity-dependent synaptic plasticity in the host striatal neurons. We evaluated synaptic plasticity in regions distal or proximal to the transplant (i.e., dorsolateral and ventrolateral striatum) and compared the effects of dopamine- and serotonin-enriched grafts using a rat model of Parkinson disease. Naïve rats showed comparable intrinsic membrane properties in the two subregions but distinct patterns of long-term synaptic plasticity. The ventrolateral striatum showed long-term potentiation using the same protocol that elicited long-term depression in the dorsolateral striatum. The long-term potentiation was linked to higher expression of postsynaptic AMPA and N2B NMDA subunits (GluN2B) and was dependent on the activation of GluN2A and GluN2B subunits and the D1 dopamine receptor. In both regions, the synaptic plasticity was abolished after a severe dopamine depletion and could not be restored by grafted serotonergic neurons. Solely, dopamine-enriched grafts could restore the long-term potentiation and partially restore motor deficits in the rats. The restoration could only be seen close to the graft, in the ventrolateral striatum where the graft-derived reinnervation was denser, compared with the distal dorsolateral region. These data provide proof of concept that dopamine-enriched transplants are able to functionally integrate into the host brain and restore deficits in striatal synaptic plasticity after experimental parkinsonism. The region-specific restoration might impose limitations in symptomatic improvement following neural transplantation.
authors.affiliation: Basal Ganglia Pathophysiological Unit, Lund University, BMC F11, 22184 Lund, Sweden.
authors.forename: Daniella
authors.initials: D
authors.lastname: Rylander
authors.forename: Vincenza
authors.initials: V
authors.lastname: Bagetta
authors.forename: Valentina
authors.initials: V
authors.lastname: Pendolino
authors.forename: Elisa
authors.initials: E
authors.lastname: Zianni
authors.forename: Shane
authors.initials: S
authors.lastname: Grealish
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Gardoni
authors.forename: Monica
authors.initials: M
authors.lastname: Di Luca
authors.forename: Paolo
authors.initials: P
authors.lastname: Calabresi
authors.forename: M Angela
authors.initials: MA
authors.lastname: Cenci
authors.forename: Barbara
authors.initials: B
authors.lastname: Picconi
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D003342:Corpus Striatum / Q000502:physiology*; D004298:Dopamine / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000637:transplantation*; D004622:Embryo, Mammalian / Q000166:cytology; D005260:Female; D007150:Immunohistochemistry; D017774:Long-Term Potentiation / Q000502:physiology; D009043:Motor Activity / Q000502:physiology; D009473:Neuronal Plasticity / Q000502:physiology*; D020734:Parkinsonian Disorders / Q000503:physiopathology* / Q000628:therapy*; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism
chemical_list: D004298:Dopamine; D017447:Receptors, Dopamine D1; D016194:Receptors, N-Methyl-D-Aspartate; C121001:NR2B NMDA receptor
keywords: 5-HT; 6-OHDA lesion; DA; LTD; LTP