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BDNF over-expression induces striatal serotonin fiber sprouting and increases the susceptibility to L-DOPA-induced dyskinesia in 6-OHDA-lesioned rats

Tronci, Elisabetta LU ; Napolitano, Francesco; Muñoz, Ana LU ; Fidalgo, Camino; Rossi, Francesca; Björklund, Anders LU ; Usiello, Alessandro and Carta, Manolo LU (2017) In Experimental Neurology 297. p.73-81
Abstract

In addition to its role in neuronal survival, the brain neurotrophic factor (BDNF) has been shown to influence serotonin transmission and synaptic plasticity, events strongly implicated in the appearance of L-DOPA-induced dyskinesia (LID), a motor complication occurring in parkinsonian patients after long-term treatment with the dopamine precursor. In order to evaluate a possible influence of BDNF in the appearance of LID, 6-OHDA-lesioned rats received a striatal injection of different concentrations of an adeno-associated viral (AAV) vector over-expressing either BDNF or GFP, as control vector. Eight weeks later, animals started to receive a daily treatment with L-DOPA (4–6 mg/kg plus benserazide 4–6 mg/kg, s.c.) or saline, and... (More)

In addition to its role in neuronal survival, the brain neurotrophic factor (BDNF) has been shown to influence serotonin transmission and synaptic plasticity, events strongly implicated in the appearance of L-DOPA-induced dyskinesia (LID), a motor complication occurring in parkinsonian patients after long-term treatment with the dopamine precursor. In order to evaluate a possible influence of BDNF in the appearance of LID, 6-OHDA-lesioned rats received a striatal injection of different concentrations of an adeno-associated viral (AAV) vector over-expressing either BDNF or GFP, as control vector. Eight weeks later, animals started to receive a daily treatment with L-DOPA (4–6 mg/kg plus benserazide 4–6 mg/kg, s.c.) or saline, and dyskinesias, as well as L-DOPA-induced rotations, were evaluated at several time-points. Moreover, molecular changes in striatal D1 receptor-dependent cAMP/PKA and ERK/mTORC signaling pathways, as well as, sprouting of striatal serotonin axons, were measured. Results showed that the AAV-BDNF vector injection induced striatal over-expression of BDNF, as well as striatal and pallidal serotonin axon hyperinnervation. Moreover, rats that over-expressed BDNF were more prone to develop LID and L-DOPA-induced rotations, compared to the GFP-treated control group. Finally, rats that over-expressed BDNF showed increased levels of striatal D1R-dependent signaling phospho-proteins in response to L-DOPA administration. This study suggests that BDNF over-expression, by inducing changes in pre-synaptic serotonin axonal trophism, is able to exacerbate maladaptive responses to L-DOPA administration.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
6-OHDA, BDNF, Dyskinesia, LID, Parkinson's disease, Serotonin, SERT
in
Experimental Neurology
volume
297
pages
9 pages
publisher
Academic Press
external identifiers
  • scopus:85026779159
  • wos:000412617300007
ISSN
0014-4886
DOI
10.1016/j.expneurol.2017.07.017
language
English
LU publication?
yes
id
7bb0f5e4-2f3e-4afc-9bb7-c8884125afd9
date added to LUP
2017-08-25 13:01:34
date last changed
2018-01-16 13:23:34
@article{7bb0f5e4-2f3e-4afc-9bb7-c8884125afd9,
  abstract     = {<p>In addition to its role in neuronal survival, the brain neurotrophic factor (BDNF) has been shown to influence serotonin transmission and synaptic plasticity, events strongly implicated in the appearance of L-DOPA-induced dyskinesia (LID), a motor complication occurring in parkinsonian patients after long-term treatment with the dopamine precursor. In order to evaluate a possible influence of BDNF in the appearance of LID, 6-OHDA-lesioned rats received a striatal injection of different concentrations of an adeno-associated viral (AAV) vector over-expressing either BDNF or GFP, as control vector. Eight weeks later, animals started to receive a daily treatment with L-DOPA (4–6 mg/kg plus benserazide 4–6 mg/kg, s.c.) or saline, and dyskinesias, as well as L-DOPA-induced rotations, were evaluated at several time-points. Moreover, molecular changes in striatal D1 receptor-dependent cAMP/PKA and ERK/mTORC signaling pathways, as well as, sprouting of striatal serotonin axons, were measured. Results showed that the AAV-BDNF vector injection induced striatal over-expression of BDNF, as well as striatal and pallidal serotonin axon hyperinnervation. Moreover, rats that over-expressed BDNF were more prone to develop LID and L-DOPA-induced rotations, compared to the GFP-treated control group. Finally, rats that over-expressed BDNF showed increased levels of striatal D1R-dependent signaling phospho-proteins in response to L-DOPA administration. This study suggests that BDNF over-expression, by inducing changes in pre-synaptic serotonin axonal trophism, is able to exacerbate maladaptive responses to L-DOPA administration.</p>},
  author       = {Tronci, Elisabetta and Napolitano, Francesco and Muñoz, Ana and Fidalgo, Camino and Rossi, Francesca and Björklund, Anders and Usiello, Alessandro and Carta, Manolo},
  issn         = {0014-4886},
  keyword      = {6-OHDA,BDNF,Dyskinesia,LID,Parkinson's disease,Serotonin,SERT},
  language     = {eng},
  month        = {11},
  pages        = {73--81},
  publisher    = {Academic Press},
  series       = {Experimental Neurology},
  title        = {BDNF over-expression induces striatal serotonin fiber sprouting and increases the susceptibility to L-DOPA-induced dyskinesia in 6-OHDA-lesioned rats},
  url          = {http://dx.doi.org/10.1016/j.expneurol.2017.07.017},
  volume       = {297},
  year         = {2017},
}