Region-specific restoration of striatal synaptic plasticity by dopamine grafts in experimental parkinsonism

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 110; no. 46; pp. E4375 - E4384
• Main Authors: Rylander, Daniella, Bagetta, Vincenza, Pendolino, Valentina, Zianni, Elisa, Grealish, Shane, Gardoni, Fabrizio, Di Luca, Monica, Calabresi, Paolo, Cenci, M Angela, Picconi, Barbara
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 12.11.2013; National Acad Sciences
• Series: PNAS Plus
• Subjects: Analysis of Variance; Animals; Basic Medicine; Biological Sciences; Blotting, Western; Corpus Striatum - physiology; Dopamine; Dopamine - metabolism; Dopaminergic Neurons - transplantation; Embryo, Mammalian - cytology; Female; Immunohistochemistry; Long-Term Potentiation - physiology; Medical and Health Sciences; Medicin och hälsovetenskap; Medicinska och farmaceutiska grundvetenskaper; Motor Activity - physiology; Neuronal Plasticity - physiology; Neurons; Neurosciences; Neurovetenskaper; Parkinson's disease; Parkinsonian Disorders - physiopathology; Parkinsonian Disorders - therapy; Patch-Clamp Techniques; PNAS Plus; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D1 - metabolism; Receptors, N-Methyl-D-Aspartate - metabolism; Rodents; Serotonin; LTP; 6-OHDA lesion; 5-HT; DA; LTD
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1311187110

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.