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BDNF Overexpression Increases Striatal D3 Receptor Level at Striatal Neurons and Exacerbates D1-Receptor Agonist-Induced Dyskinesia

Scheggi, Simona ; Rossi, Francesca ; Corsi, Sara ; Fanni, Silvia LU ; Tronci, Elisabetta LU ; Ludovica, Congiu ; Vargiu, Romina ; Gambarana, Carla ; Muñoz, Ana LU and Stancampiano, Roberto , et al. (2020) In Journal of Parkinson's Disease
Abstract

BACKGROUND: We recently showed that striatal overexpression of brain derived neurotrophic factor (BDNF) by adeno-associated viral (AAV) vector exacerbated L-DOPA-induced dyskinesia (LID) in 6-OHDA-lesioned rats. An extensive sprouting of striatal serotonergic terminals accompanied this effect, accounting for the increased susceptibility to LID.

OBJECTIVE: We set to investigate whether the BDNF effect was restricted to LID, or extended to dyskinesia induced by direct D1 receptor agonists.

METHODS: Unilaterally 6-OHDA-lesioned rats received a striatal injection of an AAV vector to induce BDNF overexpression. Eight weeks later, animals received daily treatments with a low dose of SKF82958 (0.02 mg/kg s.c.) and development of... (More)

BACKGROUND: We recently showed that striatal overexpression of brain derived neurotrophic factor (BDNF) by adeno-associated viral (AAV) vector exacerbated L-DOPA-induced dyskinesia (LID) in 6-OHDA-lesioned rats. An extensive sprouting of striatal serotonergic terminals accompanied this effect, accounting for the increased susceptibility to LID.

OBJECTIVE: We set to investigate whether the BDNF effect was restricted to LID, or extended to dyskinesia induced by direct D1 receptor agonists.

METHODS: Unilaterally 6-OHDA-lesioned rats received a striatal injection of an AAV vector to induce BDNF overexpression. Eight weeks later, animals received daily treatments with a low dose of SKF82958 (0.02 mg/kg s.c.) and development of dyskinesia was evaluated. At the end of the experiment, D1 and D3 receptors expression levels and D1 receptor-dependent signaling pathways were measured in the striatum.

RESULTS: BDNF overexpression induced significant worsening of dyskinesia induced by SKF82958 compared to the GFP group and increased the expression of D3 receptor at striatal level, even in absence of pharmacological treatment; by contrast, D1 receptor levels were not affected. In BDNF-overexpressing striata, SKF82958 administration resulted in increased levels of D1-D3 receptors co-immunoprecipitation and increased phosphorylation levels of Thr34 DARPP-32 and ERK1/2.

CONCLUSION: Here we provide evidence for a functional link between BDNF, D3 receptors and D1-D3 receptor close interaction in the augmented susceptibility to dyskinesia in 6-OHDA-lesioned rats. We suggest that D1/D3 receptors interaction may be instrumental in driving the molecular alterations underlying the appearance of dyskinesia; its disruption may be a therapeutic strategy for treating dyskinesia in PD patients.

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publication status
epub
subject
in
Journal of Parkinson's Disease
publisher
IOS Press
external identifiers
  • scopus:85095461103
  • pmid:32651332
ISSN
1877-718X
DOI
10.3233/JPD-202061
language
English
LU publication?
yes
id
1de9fd78-5359-41fb-a39f-70d06c912910
date added to LUP
2020-10-15 13:58:01
date last changed
2020-12-01 03:40:49
@article{1de9fd78-5359-41fb-a39f-70d06c912910,
  abstract     = {<p>BACKGROUND: We recently showed that striatal overexpression of brain derived neurotrophic factor (BDNF) by adeno-associated viral (AAV) vector exacerbated L-DOPA-induced dyskinesia (LID) in 6-OHDA-lesioned rats. An extensive sprouting of striatal serotonergic terminals accompanied this effect, accounting for the increased susceptibility to LID.</p><p>OBJECTIVE: We set to investigate whether the BDNF effect was restricted to LID, or extended to dyskinesia induced by direct D1 receptor agonists.</p><p>METHODS: Unilaterally 6-OHDA-lesioned rats received a striatal injection of an AAV vector to induce BDNF overexpression. Eight weeks later, animals received daily treatments with a low dose of SKF82958 (0.02 mg/kg s.c.) and development of dyskinesia was evaluated. At the end of the experiment, D1 and D3 receptors expression levels and D1 receptor-dependent signaling pathways were measured in the striatum.</p><p>RESULTS: BDNF overexpression induced significant worsening of dyskinesia induced by SKF82958 compared to the GFP group and increased the expression of D3 receptor at striatal level, even in absence of pharmacological treatment; by contrast, D1 receptor levels were not affected. In BDNF-overexpressing striata, SKF82958 administration resulted in increased levels of D1-D3 receptors co-immunoprecipitation and increased phosphorylation levels of Thr34 DARPP-32 and ERK1/2.</p><p>CONCLUSION: Here we provide evidence for a functional link between BDNF, D3 receptors and D1-D3 receptor close interaction in the augmented susceptibility to dyskinesia in 6-OHDA-lesioned rats. We suggest that D1/D3 receptors interaction may be instrumental in driving the molecular alterations underlying the appearance of dyskinesia; its disruption may be a therapeutic strategy for treating dyskinesia in PD patients.</p>},
  author       = {Scheggi, Simona and Rossi, Francesca and Corsi, Sara and Fanni, Silvia and Tronci, Elisabetta and Ludovica, Congiu and Vargiu, Romina and Gambarana, Carla and Muñoz, Ana and Stancampiano, Roberto and Björklund, Anders and Carta, Manolo},
  issn         = {1877-718X},
  language     = {eng},
  month        = {07},
  publisher    = {IOS Press},
  series       = {Journal of Parkinson's Disease},
  title        = {BDNF Overexpression Increases Striatal D3 Receptor Level at Striatal Neurons and Exacerbates D1-Receptor Agonist-Induced Dyskinesia},
  url          = {http://dx.doi.org/10.3233/JPD-202061},
  doi          = {10.3233/JPD-202061},
  year         = {2020},
}