Evidence for Dysfunction of the Nigrostriatal Pathway in the R6/1 Line of Transgenic Huntington's Disease Mice

Petersén, Åsa; Puschban, Zoe; Lotharius, Julie; NicNiocaill, Brid; Wiekop, Pia; O’Connor, W.T.; Brundin, Patrik

doi:10.1006/nbdi.2002.0534

Cited by 84 publications

(60 citation statements)

References 78 publications

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“…This impairment of nigrostriatal retrograde labelling is progressive in R6/1 mice. Whilst it has been shown previously that the uptake or transport of FG is intact in 16-weeks-old animals (Petersen et al 2002), we observed an effect at 30 weeks of age. This effect was exacerbated in bDM mice, suggesting that the lack of BDNF contributes to the progression of the neurodegenerative process in the presence of mutant htt.…”

Section: Discussioncontrasting

confidence: 91%

“…Thus, we analyzed the contents of dopamine and the levels of D 1 and D 2 receptors. We observed a significant decrease of dopamine contents in bDM compared with R6/1 mice, which did not show reduction in dopamine content, as described previously (Petersen et al 2002). These abnormal levels of dopamine in bDM could not be attributed to transport impairments because we examined dopamine content at 15 weeks of age, just before any effect on the transport or uptake of FG.…”

Section: Discussionsupporting

confidence: 87%

“…These findings are in agreement with the results obtained when R6/1 and R6/2 lines were compared. Whereas no differences in dopamine content are detected in R6/1 mice (Petersen et al 2002;present results), studies performed in homogenates of R6/2 mouse striata, in which BDNF is decreased (Zhang et al 2003), demonstrated diminished levels of dopamine (Reynolds et al 1999;Hickey et al 2002). In addition, dopamine concentration in post-mortem striatal HD tissue has been shown to be decreased (Kish et al 1987), a finding that can also be related to the reduced levels of BDNF (Ferrer et al 2000).…”

Section: Discussionmentioning

confidence: 45%

“…Several reports have shown that these mice reproduce some of the dopaminergic dysfunction observed in HD patients. However, dopaminergic deficits are more apparent in the R6/2 line (Bibb et al 2000;Hickey et al 2002;Petersen et al 2002), which shows a more rapid progression of HD symptoms (Mangiarini et al 1996). These dopaminergic alterations include decreased levels of D 1 and D 2 dopamine receptors (Cha et al 1998), reduced dopamine content (Reynolds et al 1999), and age-dependent impairment in the behavioural response to dopamine stimulants (Hickey et al 2002).…”

Section: Introductionmentioning

confidence: 99%

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Brain‐derived neurotrophic factor modulates dopaminergic deficits in a transgenic mouse model of Huntington's disease

Pineda¹,

Canals²,

Bosch³

et al. 2005

Journal of Neurochemistry

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Dysfunction of dopaminergic neurons may contribute to motor impairment in Huntington's disease. Here, we study the role of brain-derived neurotrophic factor (BDNF) in alterations of the nigrostriatal system associated with transgenics carrying mutant huntingtin. Using huntingtin-BDNF +/-double-mutant mice, we analyzed the effects of reducing the levels of BDNF expression in a model of Huntington's disease (R6/1). When compared with R6/1 mice, these mice exhibit an increased number of aggregates in the substantia nigra pars compacta. In addition, reduction of BDNF expression exacerbates the dopaminergic neuronal dysfunction seen in mutant huntingtin mice, such as the decrease in retrograde labelling of dopaminergic neurons and striatal dopamine content. However, mutant huntingtin mice with normal or lowered BDNF expression show the same decrease in the anterograde transport, number of dopaminergic neurons and nigral volume. In addition, reduced BDNF expression causes decreased dopamine receptor expression in mutant huntingtin mice. Examination of changes in locomotor activity induced by dopamine receptor agonists revealed that, in comparison with R6/1 mice, the double mutant mice exhibit lower activity in response to amphetamine, but not to apomorphine. In conclusion, these findings demonstrate that the decreased BDNF expression observed in Huntington's disease exacerbates dopaminergic neuronal dysfunction, which may participate in the motor disturbances associated with this neurodegenerative disorder. Keywords: amphetamine, axonal transport, movement disorders, neuronal dysfunction, neurotrophins, substantia nigra. J. Neurochem. (2005Neurochem. ( ) 93, 1057Neurochem. ( -1068 Neurodegenerative disorders are characterized by a progressive and specific loss of neurons. Huntington's disease (HD) is an autosomal dominant inherited neurodegenerative disorder caused by unstable expanded CAG repeats in the 5¢-coding region of the huntingtin (htt) gene (The Huntington's Disease Collaborative Research Group 1993). The primary brain region affected in HD is the striatum, where a selective degeneration of GABAergic projection neurons occurs. However, neuronal degeneration also extends to other brain areas, including the cerebral cortex, substantia nigra (SN), globus pallidus and subthalamic nucleus as the disease progresses (Rubinsztein 2002;Browne and Beal 2004).The important role of the SN dopaminergic system in the control of motor function suggests that dysfunctional dopaminergic transmission may play a role in motor disturbances, the most common feature of HD (Hickey et al. 2002). In fact, reduced expression of dopamine receptors and Received August 6, 2004; revised manuscript received December 10, 2004; accepted December 14, 2004. Address correspondence and reprint requests to Dr J. Alberch, Departament de Biologia CelAElular i Anatomia Patològica, Facultat de Medicina, Universitat de Barcelona, C/Casanova, 143 E-08036 Barcelona, Spain. E-mail: alberch@ub.eduAbbreviations used: BDA, biotinylated dextran am...

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Section: Discussioncontrasting

confidence: 91%

Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 45%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Brain‐derived neurotrophic factor modulates dopaminergic deficits in a transgenic mouse model of Huntington's disease

Pineda¹,

Canals²,

Bosch³

et al. 2005

Journal of Neurochemistry

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“…In addition, a pharmacological blockade of DA receptors resulted in a shift from 80 to 100 Hz to 50 Hz synchrony in awake mice (35), whereas injections of psychostimulants or DA agonists in normal rats produced an opposite effect of enhancement of γ-synchrony (14), as in our R6/1 mice. Taken together, these data suggest increased DA transmission in R6/1 mice, as in HD (36), whereas a decreased nigrostratal activity and DA transmission have been reported in the R6/1 mice (37,38). No explanation is currently available to reconcile this apparent discrepancy.…”

Section: Discussionmentioning

confidence: 79%

Changes in striatal procedural memory coding correlate with learning deficits in a mouse model of Huntington disease

Cayzac

Delcasso

Paz

et al. 2011

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

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In hereditary neurodegenerative Huntington disease (HD), early cognitive impairments before motor deficits have been hypothesized to result from dysfunction in the striatum and cortex before degeneration. To test this hypothesis, we examined the firing properties of single cells and local field activity in the striatum and cortex of pre-motor-symptomatic R6/1 transgenic mice while they were engaged in a procedural learning task, the performance on which typically depends on the integrity of striatum and basal ganglia. Here, we report that a dramatically diminished recruitment of the vulnerable striatal projection cells, but not local interneurons, of R6/1 mice in coding for the task, compared with WT littermates, is associated with severe deficits in procedural learning. In addition, both the striatum and cortex in these mice showed a unique oscillation at high γ-frequency. These data provide crucial information on the in vivo cellular processes in the corticostriatal pathway through which the HD mutation exerts its effects on cognitive abilities in early HD.single unit | local field potential | high γ-oscillation | operant learning | pre-motor-symptomatic R6/1 mice H untington disease (HD) is a progressive and inherited neurodegenerative disorder associated with selective degeneration of medium-sized spiny projection neurons in the striatum (1). Although the disease is well characterized by symptoms such as involuntary choreiform movements, dystonias, and rigidity, these motor symptoms have been found to be preceded by personality, mood, and cognitive disturbances (2). Some postmortem studies have also shown only limited signs of pathologic processes or cell loss in the brain despite substantial clinical evidence of HD (3), suggesting that neuronal-and, more precisely, synapticdysfunction, rather than cell death, may predominantly underlie early behavioral manifestations of the HD mutation.Studies of the effects of the mutant HD gene in several transgenic mouse models, including the R6 lines, have indeed shown changes in the membrane properties, biochemistry, and morphology of fragile striatal cells (4, 5), suggesting compromised functional integrity. They have also shown early and progressive alterations in synaptic plasticity in the corticostriatal pathway (6). These changes have been hypothesized to underlie early cognitive and behavioral deficits in transgenic mice (and patients with HD) by altering striatal information processing and transfer within basal ganglia loops.To verify this hypothesis, we recorded single-unit activity and local field potentials (LFPs) in the dorsal striatum and cortex, whereas behaviorally naive pre-motor-symptomatic R6/1 mice (7) (14-18 wk old) and age-matched WT littermates acquired an association between a nose-poke (NP) action and reward through operant learning. This procedural learning of an action-reward association is known to critically involve the striatum, a crucial site for the integration of the sensorimotor, limbic, and cognitive information required for the selecti...

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Dopamine D² receptor knockout mice develop features of Parkinson disease

Tinsley

Bye

Parish

et al. 2009

Annals of Neurology

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Evidence for Dysfunction of the Nigrostriatal Pathway in the R6/1 Line of Transgenic Huntington's Disease Mice

Cited by 84 publications

References 78 publications

Brain‐derived neurotrophic factor modulates dopaminergic deficits in a transgenic mouse model of Huntington's disease

Brain‐derived neurotrophic factor modulates dopaminergic deficits in a transgenic mouse model of Huntington's disease

Changes in striatal procedural memory coding correlate with learning deficits in a mouse model of Huntington disease

Dopamine D² receptor knockout mice develop features of Parkinson disease

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Evidence for Dysfunction of the Nigrostriatal Pathway in the R6/1 Line of Transgenic Huntington's Disease Mice

Cited by 84 publications

References 78 publications

Brain‐derived neurotrophic factor modulates dopaminergic deficits in a transgenic mouse model of Huntington's disease

Brain‐derived neurotrophic factor modulates dopaminergic deficits in a transgenic mouse model of Huntington's disease

Changes in striatal procedural memory coding correlate with learning deficits in a mouse model of Huntington disease

Dopamine D2 receptor knockout mice develop features of Parkinson disease

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Dopamine D² receptor knockout mice develop features of Parkinson disease