Differential D1 and D2 receptor-mediated effects on immediate early gene induction in a transgenic mouse model of Huntington’s disease

Spektor, Boris; Miller, David W.; Hollingsworth, Zane R.; Solano, Steven M.; Johnson, Jennifer M.; Penney, John B.; Young, Anne B.; Lüthi-Carter, Ruth

doi:10.1016/s0169-328x(02)00216-4

Cited by 44 publications

(37 citation statements)

References 75 publications

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“…In R6/2 mice, the striatal expression of the D 1 R is markedly reduced when compared with that of WT mice. However, the induction of immediate early genes by the D 1 R in the striatum of R6/2 mice is comparable to that found in WT mice [87,88]. Profound changes in electrophysiological properties and signal transduction of G-protein-coupled receptors have also been reported by different laboratories [77,78,[88][89][90][91].…”

Section: Changes In the Transcription/expression/ Function Of A 2a Rssupporting

confidence: 59%

“…However, the induction of immediate early genes by the D 1 R in the striatum of R6/2 mice is comparable to that found in WT mice [87,88]. Profound changes in electrophysiological properties and signal transduction of G-protein-coupled receptors have also been reported by different laboratories [77,78,[88][89][90][91]. It appears that many signal transduction pathways mediated by neurotransmitter receptors are aberrantly regulated because of complex compensatory mechanisms during the progression of HD.…”

Section: Changes In the Transcription/expression/ Function Of A 2a Rsmentioning

confidence: 55%

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A Critical Evaluation of Adenosine A2A Receptors as Potentially “Druggable” Targets in Huntingtons Disease

Popoli¹,

Blum²,

Domenici³

et al. 2008

CPD

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Huntington's disease (HD) is a dominantly inherited neurodegenerative disorder caused by the expansion of a polymorphic CAG trinucleotide repeat encoding a poly-glutamine tract within the Huntingtin protein. GABAergic enkephalin neurons of the basal ganglia, which show the highest levels of expression of adenosine A(2A) receptors, are the most vulnerable in HD. Such a selective neuronal vulnerability, which occurs despite ubiquitous expression of mutant and normal Huntingtin, has suggested that adenosine A(2A) receptors might play a pathogenetic role in HD. In agreement, changes in A(2A) receptor expression and signaling have been reported in various experimental models of HD. The interpretation of the functional significance of the aberrant A(2A) receptor phenotype in HD mice is however complicated by the conflicting data so far reported on the potential neuroprotective and neurodegenerative effects of these receptors in the brain, with some data suggesting a potential pathogenetic role and some other data suggesting activation of trophic or protective pathways in neurons. The same complex profile has emerged in experimental models of HD, in which both A(2A) receptor agonists and antagonists have shown beneficial effects. The main aim of this review is to critically evaluate whether adenosine A(2A) receptors may represent a suitable target to develop drugs against HD.

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Section: Changes In the Transcription/expression/ Function Of A 2a Rssupporting

confidence: 59%

Section: Changes In the Transcription/expression/ Function Of A 2a Rsmentioning

confidence: 55%

A Critical Evaluation of Adenosine A2A Receptors as Potentially “Druggable” Targets in Huntingtons Disease

Popoli¹,

Blum²,

Domenici³

et al. 2008

CPD

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“…Notably, Egr-1 levels are specifically decreased in the dorsal subregion of the striatum in R6/2 mouse model of HD (Spektor et al, 2002) and are elevated in the striatum after exposure to drugs of abuse (Valjent et al, 2000(Valjent et al, , 2006. More important perhaps is the potential contribution to cell replacement therapy and to the use of induced pluripotent stem (iPS) cells for the study of disease mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Egr-1 Induces DARPP-32 Expression in Striatal Medium Spiny Neurons via a Conserved Intragenic Element

et al. 2012

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DARPP-32 (dopamine and adenosine 3Ј, 5Ј-cyclic monophosphate cAMP-regulated phosphoprotein, 32 kDa) is a striatal-enriched protein that mediates signaling by dopamine and other first messengers in the medium spiny neurons. The transcriptional mechanisms that regulate striatal DARPP-32 expression remain enigmatic and are a subject of much interest in the efforts to induce a striatal phenotype in stem cells. We report the identification and characterization of a conserved region, also known as H10, in intron IV of the gene that codes for DARPP-32 (Ppp1r1b). This DNA sequence forms multiunit complexes with nuclear proteins from adult and embryonic striata of mice and rats. Purification of proteins from these complexes identified early growth response-1 (Egr-1). The interaction between Egr-1 and H10 was confirmed in vitro and in vivo by super-shift and chromatin immunoprecipitation assays, respectively. Importantly, brain-derived neurotrophic factor (BDNF), a known inducer of DARPP-32 and Egr-1 expression, enhanced Egr-1 binding to H10 in vitro. Moreover, overexpression of Egr-1 in primary striatal neurons induced the expression of DARPP-32, whereas a dominantnegative Egr-1 blocked DARPP-32 induction by BDNF. Together, this study identifies Egr-1 as a transcriptional activator of the Ppp1r1b gene and provides insight into the molecular mechanisms that regulate medium spiny neuron maturation.

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“…Although this result was unexpected, it suggests that the reduced dopaminergic input induces sensitization of D 1 and/or D 2 receptors in the striatum in HD. Supersensitization of D 1 receptors has also been postulated in R6/2 mice, which shows decrease of dopamine receptor expression (Cha et al 1998) but no decrease in immediate early gene expression induced by a D 1 agonist (Spektor et al 2002).…”

Section: Discussionmentioning

confidence: 99%

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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Differential D1 and D2 receptor-mediated effects on immediate early gene induction in a transgenic mouse model of Huntington’s disease

Cited by 44 publications

References 75 publications

A Critical Evaluation of Adenosine A2A Receptors as Potentially “Druggable” Targets in Huntingtons Disease

A Critical Evaluation of Adenosine A2A Receptors as Potentially “Druggable” Targets in Huntingtons Disease

Egr-1 Induces DARPP-32 Expression in Striatal Medium Spiny Neurons via a Conserved Intragenic Element

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

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Differential D1 and D2 receptor-mediated effects on immediate early gene induction in a transgenic mouse model of Huntington’s disease

Cited by 44 publications

References 75 publications

A Critical Evaluation of Adenosine A2A Receptors as Potentially &#x201C;Druggable&#x201D; Targets in Huntingtons Disease

A Critical Evaluation of Adenosine A2A Receptors as Potentially &#x201C;Druggable&#x201D; Targets in Huntingtons Disease

Egr-1 Induces DARPP-32 Expression in Striatal Medium Spiny Neurons via a Conserved Intragenic Element

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

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A Critical Evaluation of Adenosine A2A Receptors as Potentially “Druggable” Targets in Huntingtons Disease

A Critical Evaluation of Adenosine A2A Receptors as Potentially “Druggable” Targets in Huntingtons Disease