Research PaperBDNF over-expression induces striatal serotonin fiber sprouting and increases the susceptibility to l-DOPA-induced dyskinesia in 6-OHDA-lesioned rats
Introduction
l-DOPA-induced dyskinesia (LID) is a troublesome side effect that develops in the vast majority of parkinsonian patients under chronic l-DOPA treatment. In recent years, the serotonin system has emerged as a key player in the appearance of LIDs and became a possible target for pharmacological therapies (Bastide et al., 2015, Carta et al., 2007). Indeed, an increasing body of experimental evidence suggests that serotonin neurons can convert l-DOPA into dopamine (DA) and mediate its release as a “false” transmitter. Due to the lack of pre-synaptic mechanisms able to fine-tune l-DOPA-derived DA release, serotonin neurons would contribute to swings in extracellular DA levels after oral administration of l-DOPA, causing, in turn, a pulsatile stimulation of striatal DA receptors, a key event in the appearance of abnormal movements (Arai et al., 1995, Carta et al., 2007, Carta and Tronci, 2014, Iderberg et al., 2015, Tanaka et al., 1999). In agreement with this scenario, toxin lesion or pharmacological blockade of serotonin neuronal activity lead to almost full suppression of LID in experimental animal models of Parkinson's disease (PD) (Beaudoin-Gobert et al., 2015, Carta et al., 2007, Muñoz et al., 2008). In line with this evidence, it has been recently demonstrated that LIDs are correlated with the state of the serotonin innervation at striatal level in the rat experimental model of PD as well as in parkinsonian patients; in fact, sprouting of serotonin neuron terminals can further exacerbate development of LID in parkinsonian rats (Rylander et al., 2010).
Rylander et al. have shown that LID correlates with striatal levels of brain-derived neurotrophic factor (BDNF) in 6-OHDA-lesioned rats; this result is in agreement with several studies, which reported that behavioral sensitization to l-DOPA in 6-OHDA-lesioned rats was associated to an upregulation of mRNA levels for BDNF and TrkB receptor in the frontal cortex and striatum (Bordet et al., 1997, Guillin et al., 2003, Guillin et al., 2001). Furthermore, several studies suggested that BDNF can produce local trophic effect on serotonergic neurons in the adult intact rat brain, when directly injected as protein (Goggi et al., 2002, Mamounas et al., 2000).
Based on the above evidence, we speculated that striatal injection of an adeno-associated viral (AAV) vector coding for the rat BDNF gene in 6-OHDA-lesioned rats, by over-expressing the neurotrophin, would induce sprouting of serotonin axons, in turn, promoting maladaptive responses to l-DOPA administration and worsening of LID. Here, sprouting of serotonin axons was measured in terms of SERT immunoreactivity, which is considered a reliable index of increased density of 5-HT-positive fibers or axonal varicosities (Bez et al., 2016, Descarries et al., 1995, Rylander et al., 2010). Moreover, based on the existence of a correlation between LID and D1 receptor-dependent cAMP/PKA and ERK/mTORC signaling pathways (Brugnoli et al., 2016, Decressac and Björklund, 2013, Santini et al., 2009b, Santini et al., 2007, Subramaniam et al., 2011), we performed biochemical analysis in order to clarify the molecular features underlying the behavioral effects observed in this study.
Section snippets
Production of the recombinant AAV viral vector
Transfer plasmids carrying adeno-associated viral (AAV5) inverted terminal repeat coding for either rat BDNF or enhanced green fluorescent protein (GFP), downstream of a cytomegalovirus enhancer hybrid synthetic chicken β-actin (CBA) promoter, were generated. Transfection into HEK 293 cells was carried out using the calcium phosphate method, and included the appropriate transfer plasmid encoding-enhanced BDNF or GFP and the packaging plasmids pDP5 encoding for the AAV5 capsid proteins. Cells
Effect of BDNF over-expression on l-DOPA-induced dyskinesia and rotation
A first experiment was performed using an undiluted BDNF vector (Exp. 1). As shown in Fig. 2A, repeated administration of l-DOPA (6 mg/kg, plus benserazide 6 mg/kg, s.c., n = 8/group) induced development of dyskinesia in both BDNF and GFP over-expressing rats during the course of the treatment. However, rats that over-expressed BDNF showed a higher susceptibility to develop dyskinesia, during the first four l-DOPA injections, as compared to GFP control animals, while this difference disappeared
Discussion
This study demonstrates for the first time that striatal injection of an AAV vector coding for the rat BDNF gene induced long-term over-expression of the neurotrophin, as well as striatal and pallidal serotonin axon hyperinnervation in 6-OHDA-lesioned rats, as measured by SERT immunostaining. Moreover, administration of l-DOPA to these rats resulted in increased susceptibility to development of LID. The exacerbation of LID in the BDNF over-expressing rats was also accompanied by up-regulation
Acknowledgments
We thank Ulla Jarl and Jenny G. Johansson for expert technical assistance. This work was supported by grants from the Italian Ministry of Education, University and Research, Progetto di Ricerca di Interesse Nazionale (PRIN) 2010-AHHP5H, and from Parkinsonfonden, Sweden.
References (48)
- et al.
l-DOPA is converted to dopamine in serotonergic fibers of the striatum of the rat: a double-labeling immunofluorescence study
Neurosci. Lett.
(1995) - et al.
Differential contribution of BDNF and NGF to long-term potentiation in the superior cervical ganglion of the rat
Neuropharmacology
(2014) - et al.
Pathophysiology of l-dopa-induced motor and non-motor complications in Parkinson's disease
Prog. Neurobiol.
(2015) - et al.
Dramatic differences in susceptibility to l-DOPA-induced dyskinesia between mice that are aged before or after a nigrostriatal dopamine lesion
Neurobiol. Dis.
(2016) - et al.
Neurotrophic factors increase axonal growth after spinal cord injury and transplantation in the adult rat
Exp. Neurol.
(1997) - et al.
Genetic deletion of Rhes or pharmacological blockade of mTORC1 prevent striato-nigral neurons activation in levodopa-induced dyskinesia
Neurobiol. Dis.
(2016) - et al.
Modulation of neurotransmitter release induced by brain-derived neurotrophic factor in rat brain striatal slices in vitro
Brain Res.
(2002) - et al.
Brain-derived neurotrophic factor controls dopamine D3 receptor expression: therapeutic implications in Parkinson's disease
Eur. J. Pharmacol.
(2003) - et al.
Activity of serotonin 5-HT(1A) receptor “biased agonists” in rat models of Parkinson's disease and l-DOPA-induced dyskinesia
Neuropharmacology
(2015) - et al.
Striatal inhibition of PKA prevents levodopa-induced behavioural and molecular changes in the hemiparkinsonian rat
Neurobiol. Dis.
(2010)
Serotonin neuron-dependent and -independent reduction of dyskinesia by 5-HT1A and 5-HT1B receptor agonists in the rat Parkinson model
Exp. Neurol.
Effects of NGF and BDNF on baseline glutamate and dopamine release in the hippocampal formation of the adult rat
Brain Res.
ERK phosphorylation and FosB expression are associated with l-DOPA-induced dyskinesia in hemiparkinsonian mice
Biol. Psychiatry
Amphetamine-induced rotation and l-DOPA-induced dyskinesia in the rat 6-OHDA model: a correlation study
Neurosci. Res.
5-Hydroxy-tryptophan for the treatment of l-DOPA-induced dyskinesia in the rat Parkinson's disease model
Neurobiol. Dis.
Effect of memantine on l-DOPA-induced dyskinesia in the 6-OHDA-lesioned rat model of Parkinson's disease
Neuroscience
Effect of selective and non-selective serotonin receptor activation on l-DOPA-induced therapeutic efficacy and dyskinesia in parkinsonian rats
Behav. Brain Res.
Spatiotemporal pattern of striatal ERK1/2 phosphorylation in a rat model of l-DOPA-induced dyskinesia and the role of dopamine D1 receptors
Biol. Psychiatry
Brain-derived neurotrophic factor rapidly increases NMDA receptor channel activity through Fyn-mediated phosphorylation
Brain Res.
Repeated l-DOPA treatment increases c-fos and BDNF mRNAs in the subthalamic nucleus in the 6-OHDA rat model of Parkinson's disease
Brain Res.
Behavioural impact of a double dopaminergic and serotonergic lesion in the non-human primate
Brain
Induction of dopamine D3 receptor expression as a mechanism of behavioral sensitization to levodopa
Proc. Natl. Acad. Sci. U. S. A.
Serotonin system implication in l-DOPA-induced dyskinesia: from animal models to clinical investigations
Front. Neurol.
Dopamine released from 5-HT terminals is the cause of l-DOPA-induced dyskinesia in parkinsonian rats
Brain
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