BDNF Overexpression Increases Striatal D3 Receptor Level at Striatal Neurons and Exacerbates D1-Receptor Agonist-Induced Dyskinesia
(2020) In Journal of Parkinson's Disease 10(4). p.1503-1514- 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.
(Less)
- author
- Scheggi, Simona
; Rossi, Francesca
; Corsi, Sara
; Fanni, Silvia
LU
; Tronci, Elisabetta
LU
; Ludovica, Congiu
; Vargiu, Romina
; Gambarana, Carla
; Muñoz, Ana
LU
; Stancampiano, Roberto
; Björklund, Anders
LU
and Carta, Manolo
LU
(Less) - organization
- publishing date
- 2020-07-08
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Journal of Parkinson's Disease
- volume
- 10
- issue
- 4
- pages
- 12 pages
- publisher
- IOS Press
- external identifiers
-
- pmid:32651332
- scopus:85095461103
- 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
- 2024-05-30 23:44:08
@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}},
number = {{4}},
pages = {{1503--1514}},
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}},
volume = {{10}},
year = {{2020}},
}