Brain Neurotransmitter Deficits in Mice Transgenic for the Huntington’s Disease Mutation

Reynolds, Gavin P.; Dalton, Caroline; Tillery, Claire L.; Mangiarini, Laura; Davies, Stephen; Bates, Gillian P.

doi:10.1046/j.1471-4159.1999.721773.x

Cited by 85 publications

(86 citation statements)

References 24 publications

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“…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: 77%

“…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).The mechanism underlying HD pathogenesis remains to be elucidated, but it could involve the gain of toxic functions, the loss of beneficial functions of wild type (wt)-htt or both. Wt-htt increases the transcription of the brain-derived neurotrophic factor (BDNF) (Zuccato et al 2001), a neuroprotective factor for striatal (Bemelmans et al 1999;Perez-Navarro et al 1999Kells et al 2004) and dopaminergic neurons (Hyman et al 1991).…”

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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: Discussionmentioning

confidence: 77%

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confidence: 99%

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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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“…A reduction of dopamine metabolites was also observed in human SCA3 cases (Higgins et al, 1996), as well as in transgenic mouse models of HD (Reynolds et al, 1999;Duan et al, 2004) and HD patients (Reynolds and Garrett, 1986). Interestingly, normalization of observed serotonin deficits in HD mice delayed neurodegeneration (Reynolds et al, 1999;Duan et al, 2004).…”

Section: Discussionmentioning

confidence: 81%

Nuclear Localization of Ataxin-3 Is Required for the Manifestation of Symptoms in SCA3:In VivoEvidence

Bichelmeier¹,

Schmidt²,

Hübener³

et al. 2007

J. Neurosci.

185

177

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Spinocerebellar ataxia type 3 (SCA3)is an autosomal dominantly inherited neurodegenerative disorder caused by the expansion of a CAG repeat in the MJD1 gene resulting in an expanded polyglutamine repeat in the ataxin-3 protein. To study the course of the disease, we generated transgenic mice for SCA3 using full-length ataxin-3 constructs containing 15, 70, or 148 CAG repeats, respectively. Control mice (15 CAGs) were phenotypically normal and had no neuropathological findings. However, mice transgenic for ataxin-3 with expanded polyglutamine repeats were severely affected by a strong neurological phenotype with tremor, behavioral deficits, strongly reduced motor and exploratory activity, a hunchback, and premature death at 3 to 6 months of age. Neuropathological examination by immunohistochemical staining revealed ubiquitin-and ataxin-3-positive intranuclear inclusion bodies in a multitude of neurons. Directing ataxin-3 with 148 CAGs to the nucleus revealed an even more pronounced phenotype with more inclusions and earlier death, whereas mice transgenic with the same construct but attached to a nuclear export signal developed a milder phenotype with less inclusions. These studies indicate that nuclear localization of ataxin-3 is required for the manifestation of symptoms in SCA3 in vivo.

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“…It has been reported that levels of serotonin and BDNF are decreased in HD mice (Reynolds et al, 1999, Zuccato et al, 2001) and HD patients (Ferrer et al, 2000;. There is a reciprocal interaction between BDNF and serotonergic signaling, in which BDNF enhances serotonin production and release, while serotonin stimulates BDNF production .…”

Section: Discussionmentioning

confidence: 99%

The antidepressant sertraline improves the phenotype, promotes neurogenesis and increases BDNF levels in the R6/2 Huntington's disease mouse model

Masuda

Jiang

et al. 2008

Experimental Neurology

158

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Huntington's disease (HD) is an inherited progressive neurodegenerative disorder characterized by progressive movement, psychiatric and cognitive disturbances. Previous studies have indicated that HD pathogenesis may be mediated in part by loss of brain derived neurotrophic factor (BDNF). Antidepressants selectively blocking serotonin reuptake can increase BDNF levels, and also may increase neurogenesis. Here we report that an SSRI antidepressant, sertraline, prolongs survival, improves motor performance, and ameliorates brain atrophy in the R6/2 HD mouse model. Six-weekold R6/2 mice and nontransgenic control mice were administered either sertraline or vehicle daily. Motor function was assessed in an accelerating rotarod test and evaluated at 10 weeks. R6/2 mice exhibited reduced time on the rod. Sertraline treatment improved the motor performance in R6/2 mice, but did not affect nontransgenic mice. R6/2 mice showed significant striatal atrophy which was reduced by sertraline treatment. These beneficial effects of sertraline are associated with enhanced neurogenesis and increased BDNF levels in brain treated with sertraline. The effective serum and brain levels of sertraline are comparable to the levels achieved in human antidepressant treatment. Our findings provide evidence that sertraline is neuroprotective in this HD model. Successful treatment with sertraline in depressed HD patients has been reported; moreover, sertraline is safe and well-tolerated for long-term administration, including in HD patients. Our findings suggest that a clinical trial of SSRI treatment in order to retard disease progression in human HD may be warranted.

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Brain Neurotransmitter Deficits in Mice Transgenic for the Huntington’s Disease Mutation

Cited by 85 publications

References 24 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

Nuclear Localization of Ataxin-3 Is Required for the Manifestation of Symptoms in SCA3:In VivoEvidence

The antidepressant sertraline improves the phenotype, promotes neurogenesis and increases BDNF levels in the R6/2 Huntington's disease mouse model

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