Personne : Gagnon, Dave
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Gagnon
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Dave
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Département de neurobiologie, Faculté de médecine, Université Laval
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Publication Accès libre Evidence for sprouting of dopamine and serotonin axons in the pallidum of Parkinsonian monkeys(Frontiers Research Foundation, 2018-05-15) Gagnon, Dave; Whissel, Carl; Di Paolo, Thérèse; Parent, Martin; Eid, Lara; Parent, André; Coudé, DymkaThis light and electron microscopie immunohistochemical quantitative study aimed at determining the state of the dopamine (DA) and serotonin (5-HT) innervations of the internal (GPi) and external (GPe) segments of the pallidum in cynomolgus monkeys (Macaca fascicularis) rendered parkinsonian by systemic injections of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In contrast to the prominent DA denervation of striatum, the GPi in MPTP monkeys was found to be markedly enriched in DA (TH+) axon varicosities. The posterior sensorimotor region of this major output structure of the basal ganglia was about 8 times more intensely innervated in MPTP monkeys (0.71 ± 0.08 × 106 TH+ axon varicosities/mm3) than in controls (0.09 ± 0.01 × 106). MPTP intoxication also induced a two-fold increase in the density of 5-HT (SERT+) axon varicosities in both GPe and GPi. This augmentation was particularly pronounced anteriorly in the so-called associative and limbic pallidal territories. The total length of the labeled pallidal axons was also significantly increased in MPTP monkeys compared to controls, but the number of DA and 5-HT axon varicosities per axon length unit remained the same in the two groups, indicating that the DA and 5-HT pallidal hyperinnervations seen in MPTP monkeys result from axon sprouting rather than from the appearance of newly formed axon varicosities on non-growing axons. At the ultrastructural level, pallidal TH+ and SERT+ axons were morphologically similar in MPTP and controls, and their synaptic incidence was very low suggesting a volumic mode of transmission. Altogether, our data reveal a significant sprouting of DA and 5-HT pallidal afferents in parkinsonian monkeys, the functional significance of which remains to be determined. We suggest that the marked DA hyperinnervation of the GPi represents a neuroadaptive change designed to normalize pallidal firing patterns associated with the delayed appearance of motor symptoms, whereas the 5-HT hyperinnervation might be involved in the early expression of non-motor symptoms in Parkinson's disease.Publication Accès libre Striatal neurons expressing D1 and D2 receptors are morphologically distinct and differently affected by dopamine denervation in mice(Nature Publishing Group, 2017-01-27) Gagnon, Dave; De Koninck, Yves; Beaulieu, Jean Martin; Sánchez, Maria Gabriela; Parent, Martin; Petryszyn, Sarah; Parent, André; Bories, CyrilThe loss of nigrostriatal dopamine neurons in Parkinson’s disease induces a reduction in the number of dendritic spines on medium spiny neurons (MSNs) of the striatum expressing D1 or D2 dopamine receptor. Consequences on MSNs expressing both receptors (D1/D2 MSNs) are currently unknown. We looked for changes induced by dopamine denervation in the density, regional distribution and morphological features of D1/D2 MSNs, by comparing 6-OHDA-lesioned double BAC transgenic mice (Drd1a-tdTomato/Drd2-EGFP) to sham-lesioned animals. D1/D2 MSNs are uniformly distributed throughout the dorsal striatum (1.9% of MSNs). In contrast, they are heterogeneously distributed and more numerous in the ventral striatum (14.6% in the shell and 7.3% in the core). Compared to D1 and D2 MSNs, D1/D2 MSNs are endowed with a smaller cell body and a less profusely arborized dendritic tree with less dendritic spines. The dendritic spine density of D1/D2 MSNs, but also of D1 and D2 MSNs, is significantly reduced in 6-OHDA-lesioned mice. In contrast to D1 and D2 MSNs, the extent of dendritic arborization of D1/D2 MSNs appears unaltered in 6-OHDA-lesioned mice. Our data indicate that D1/D2 MSNs in the mouse striatum form a distinct neuronal population that is affected differently by dopamine deafferentation that characterizes Parkinson’s disease.Publication Restreint Serotonin hyperinnervation of the striatum with high synaptic incidence in parkinsonian monkeys(Springer, 2015-10-13) Gagnon, Dave; Di Paolo, Thérèse; Parent, Martin; Grégoire, LaurentThe chronic use of L-Dopa for alleviating the motor symptoms of Parkinson’s disease often produces adverse effects such as dyskinesia. Unregulated release of dopamine by serotonin axons following L-Dopa administration is a major presynaptic determinant of these abnormal involuntary movements. The present study was designed to characterize the reorganization of serotonin striatal afferents following dopaminergic denervation in a primate model of Parkinson’s disease. Our sample comprised eight cynomolgus monkeys: four that were rendered parkinsonian following MPTP administration and four controls. The state of striatal serotonin and dopamine innervation was evaluated by means of immunohistochemistry with antibodies against serotonin transporter (SERT) and tyrosine hydroxylase. A detailed stereological investigation revealed a significant increase in the number of serotonin axon varicosities in the striatum of MPTP-intoxicated monkeys. This increase is particularly pronounced in the sensorimotor territory of the striatum, where the dopamine denervation is the most severe. Electron microscopic examinations indicate that, in contrast to the nucleus accumbens where the dopamine innervation is preserved, the SERT+ axon varicosities observed in the sensorimotor territory of the putamen establish twice as many synaptic contacts in MPTP-intoxicated monkeys than in controls. These findings demonstrate the highly plastic nature of the serotonin striatal afferent projections, a feature that becomes particularly obvious in the absence of striatal dopamine. Although the number of dorsal raphe serotonin neurons remains constant in parkinsonian monkeys, as shown in the present study, their ascending axonal projections undergo marked proliferative and synaptic adaptive changes that might play a significant role in the potential unregulated and ectopic release of dopamine by serotonin axons after L-Dopa treatment of Parkinson’s disease.