3,4-Dihydroxyphenylalanine Reverses the Motor Deficits in Pitx3-Deficient<i>Aphakia</i>Mice: Behavioral Characterization of a Novel Genetic Model of Parkinson's Disease

Hwang, Deuk-Soo; Fleming, Sheila M.; Ardayfio, Paul; Moran-Gates, Taylor; Kim, Han‐Soo; Tarazi, Frank I.; Chesselet, Marie‐Françoise; Kim, Kwangsoo

doi:10.1523/jneurosci.3718-04.2005

Cited by 164 publications

(175 citation statements)

References 24 publications

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supporting

confidence: 63%

“…Fourth, Pitx3 ak/ak mice lack nigrostriatal DA projections throughout development, which may favor the conditions for LID induction, as human PD patients with early-age onset and children with an impaired ability to produce DA show more pronounced LID than those who develop the condition later in life (16,17). Consistent with this view, the molecular and cellular measures of LID seen in lesion models have also been demonstrated in Pitx3 ak/ak mice (12,13,(18)(19)(20).In this article, we investigated the effects of acute and repeated L-DOPA treatment on striatal ERK phosphorylation, and tested its role in akinesia improvement and LID expression in Pitx3 ak/ak mice and in a unilateral parkinsonian mouse model. Our behavioral, anatomical, and electrophysiological investigations support a critical role of striatal cholinergic neurons in the expression of LID.…”

mentioning

confidence: 69%

“…The lack of transcription factor Pitx3 results in selective loss of nigrostriatal DA projections in a remarkably similar pattern to the neuroanatomical features of PD along with parkinsonian motor deficits (10,(12)(13)(14)(15). There are several advantages and complementary features of the Pitx3 ak/ak mouse over the more traditional PD models involving toxininduced unilateral lesion.…”

mentioning

confidence: 98%

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Enhanced striatal cholinergic neuronal activity mediatesl-DOPA–induced dyskinesia in parkinsonian mice

Ding¹,

Won²,

Britt

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

173

192

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Treatment of Parkinson disease (PD) with L-3,4-dihydroxyphenylalanine (L-DOPA) dramatically relieves associated motor deficits, but L-DOPA-induced dyskinesias (LID) limit the therapeutic benefit over time. Previous investigations have noted changes in striatal medium spiny neurons, including abnormal activation of extracellular signal-regulated kinase1/2 (ERK). Using two PD models, the traditional 6-hydroxydopamine toxic lesion and a genetic model with nigrostriatal dopaminergic deficits, we found that acute dopamine challenge induces ERK activation in medium spiny neurons in denervated striatum. After repeated L-DOPA treatment, however, ERK activation diminishes in medium spiny neurons and increases in striatal cholinergic interneurons. ERK activation leads to enhanced basal firing rate and stronger excitatory responses to dopamine in striatal cholinergic neurons. Pharmacological blockers of ERK activation inhibit L-DOPA-induced changes in ERK phosphorylation, neuronal excitability, and the behavioral manifestation of LID. In addition, a muscarinic receptor antagonist reduces LID. These data indicate that increased dopamine sensitivity of striatal cholinergic neurons contributes to the expression of LID, which suggests novel therapeutic targets for LID.antagonist D opaminergic drugs are effective treatments for the motor symptoms of Parkinson disease (PD), but long-term therapy is limited by disabling abnormal involuntary movements, referred to as L-DOPA-induced dyskinesias (LID) (1). Thus, understanding the molecular and cellular mechanisms underlying LID will help identify more effective treatments for PD, and may also help elucidate the role of dopamine (DA) signaling in motor control.Several biochemical markers of LID have been studied in striatum using animal models. FosB/δFosB expression show a long-term temporal correlation with LID development in DA denervation PD models (2). The increased FosB expression persists over days or weeks and may contribute to the development of LID, but does not correlate with the L-DOPA-induced episodes of dyskinesia that follow each dose. To mediate expression of LID directly, cell signals should grow stronger with repeated L-DOPA treatment and show temporal correlation with acute dopaminergic stimulation. Acute administration of L-DOPA or dopamine agonists activates ERK1/2 by phosphorylation in striatal neurons of DA-denervated animals (3-7). In animals with unilateral 6-hydroxydopamine (6-OHDA) lesions, coadministration of inhibitors of ERK1/2 phosphorylation during repeated L-DOPA treatments reduce LID development (4,8). Studies on these molecular changes have focused on the predominant cell type in the striatum, medium spiny neurons (MSN). In addition, although the unilateral 6-OHDA lesion has been the standard model for the PD phenotype, and particularly for LID, the abrupt nature of the lesion and extreme depletion of dopaminergic afferents has posed limitations in behavioral and biochemical studies.In this study, we used both a unilateral 6-OHDA lesion model and a g...

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supporting

confidence: 63%

mentioning

confidence: 69%

mentioning

confidence: 98%

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Enhanced striatal cholinergic neuronal activity mediatesl-DOPA–induced dyskinesia in parkinsonian mice

Ding¹,

Won²,

Britt

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

173

192

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“…However, we were unable to detect any sign of behavioral parkinsonism after paraquat, even though we used a battery of tests that are exquisitely sensitive to nigrostriatal dysfunction in mice (Hwang et al, 2005). The lack of behavioral deficit after paraquat administration is not surprising in view of the small magnitude of neuronal loss and even smaller loss of THpositive terminals in the striatum.…”

Section: Effects Of Paraquat On Catecholaminergic Neuronsmentioning

confidence: 84%

Behavioral and histopathological consequences of paraquat intoxication in mice: Effects of α‐synuclein over‐expression

Fernagut

Hutson

Fleming

et al. 2007

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Genetic variability in the α-synuclein gene and long-term exposure to the pesticide paraquat constitute possible risk factors for sporadic Parkinson's disease. The goal of the present study was to further characterize the effects of paraquat in mice as a model of Parkinson's disease and to determine whether it acted synergistically with α-synuclein over-expression to cause nigrostriatal cell death or dysfunction. Paraquat (10 mg/kg i.p.) was administered once a week for 3 weeks to mice over-expressing human α-synuclein under the Thy1 promoter and their wild-type littermates. The effect of paraquat on catecholaminergic neurons was reminiscent of that of Parkinson's disease, with preferential loss of dopaminergic neurons in the ventral tier of the substantia nigra pars compacta and loss of tyrosine hydroxylase staining in the locus coeruleus. α-Synuclein overexpression did not increase paraquat-induced cell loss, and paraquat did not worsen the behavioral deficits observed in the transgenic mice. However, paraquat markedly increased proteinase-Kresistant α-synuclein aggregates in substantia nigra of the transgenic mice. The data further validate the use of paraquat to model Parkinson's disease in mice and show that although paraquat and α-synuclein over-expression act synergistically to increase protein aggregation in vivo, this interaction does not result in short-term neuroprotection or increased vulnerability of nigrostriatal neurons.

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“…In homozygote ak mice, SNc cell loss (particularly in the ventral nigra) is almost complete by birth, whereas the ventral tegmental area (VTA) undergoes progressive postnatal cell loss (Nunes et al, 2003;van den Munckhof et al, 2003) so that approximately 50% of this region is lost by 100 days (van den Munckhof et al, 2003). Ak mice exhibit relatively subtle behavioral and motor deficits (Hwang et al, 2003;van den Munckhof et al, 2003;, and some conflicting data exist in this regard (Smidt et al, 2004;Hwang et al, 2005). It is not known whether motor signs progress with age in ak mice.…”

Section: Introductionmentioning

confidence: 99%

Motor deficits and altered striatal gene expression in aphakia (ak) mice

et al. 2007

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Like humans with Parkinsons disease (PD), the ak mouse lacks the majority of the substantia nigra pars compacta (SNc) and experiences striatal denervation. The purpose of this study was to test whether motor abnormalities in the ak mouse progress over time, and whether motor function could be associated with temporal alterations in the striatal transcriptome. Ak and wt mice (28 to 180 days old) were tested using paradigms sensitive to nigrostriatal dysfunction. Results were analyzed using a linear mixed model. Ak mice significantly underperformed wt controls in rotarod, balance beam, string test, pole test and cotton shred tests at all ages examined. Motor performance in ak mice remained constant over the first 6 months of life, with the exception of the cotton shred test, in which ak mice exhibited marginal decline in performance. Dorsal striatal semi-quantitative RT-PCR for 19 dopaminergic, cholinergic, glutaminergic and catabolic genes was performed in 1 and 6 month old groups of ak and wt mice. Preproenkephalin levels in ak mice were elevated in both age groups. Drd1, 3 and 4 levels declined over time, in contrast to increasing Drd2 expression. Additional findings included decreased Chrnα6 expression and elevated VGluT1 expression at both time points in ak mice, and elevated AchE expression in young ak mice only. Results confirm that motor ability does not decline significantly for the first 6 months of life in ak mice. Their striatal gene expression patterns are consistent with dopaminergic denervation, and change over time, despite relatively unaltered motor performance.

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3,4-Dihydroxyphenylalanine Reverses the Motor Deficits in Pitx3-DeficientAphakiaMice: Behavioral Characterization of a Novel Genetic Model of Parkinson's Disease

Cited by 164 publications

References 24 publications

Enhanced striatal cholinergic neuronal activity mediatesl-DOPA–induced dyskinesia in parkinsonian mice

Enhanced striatal cholinergic neuronal activity mediatesl-DOPA–induced dyskinesia in parkinsonian mice

Behavioral and histopathological consequences of paraquat intoxication in mice: Effects of α‐synuclein over‐expression

Motor deficits and altered striatal gene expression in aphakia (ak) mice

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