Expression of Brain-Derived Neurotrophic Factor in Cortical Neurons Is Regulated by Striatal Target Area

Canals, Josep M.; Checa, Núria; Marco, Sonia; Åkerud, Peter; Michels, Alice; Pérez‐Navarro, Esther; Tolosa, Eduard; Arenas, Ernest; Alberch, Jordi

doi:10.1523/jneurosci.21-01-00117.2001

Cited by 98 publications

(79 citation statements)

References 52 publications

(63 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Serial coronal cryostat sections (14 m) were processed for hybridization with radioactive riboprobes (Ibanez et al, 1992;Laurenzi et al, 1994;Lindefors et al, 1995) as described previously (Canals et al, 2001). Antisense cRNA probe to detect the transcripts of neurotrophins was prepared by in vitro transcription using T3 or T7 RNA polymerase (Promega) and […”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Brain-Derived Neurotrophic Factor Regulates the Onset and Severity of Motor Dysfunction Associated with Enkephalinergic Neuronal Degeneration in Huntington's Disease

Canals¹,

Pineda²,

et al. 2004

View full text Add to dashboard Cite

The mechanism that controls the selective vulnerability of striatal neurons in Huntington's disease is unclear. Brain-derived neurotrophic factor (BDNF) protects striatal neurons and is regulated by Huntingtin through the interaction with the neuron-restrictive silencer factor. Here, we demonstrate that the downregulation of BDNF by mutant Huntingtin depends on the length and levels of expression of the CAG repeats in cell cultures. To analyze the functional effects of these changes in BDNF in Huntington's disease, we disrupted the expression of bdnf in a transgenic mouse model by cross-mating bdnf ϩ/Ϫ mice with R6/1 mice. Thus, we compared transgenic mice for mutant Huntingtin with different levels of BDNF. Using this double mutant mouse line, we show that the deficit of endogenous BDNF modulates the pathology of Huntington's disease. The decreased levels of this neurotrophin advance the onset of motor dysfunctions and produce more severe uncoordinated movements. This behavioral pathology correlates with the loss of striatal dopamine and cAMPregulated phosphoprotein-32-positive projection neurons. In particular, the insufficient levels of BDNF cause specific degeneration of the enkephalinergic striatal projection neurons, which are the most affected cells in Huntington's disease. This neuronal dysfunction can specifically be restored by administration of exogenous BDNF.Therefore, the decrease in BDNF levels plays a key role in the specific pathology observed in Huntington's disease by inducing dysfunction of striatal enkephalinergic neurons that produce severe motor dysfunctions. Hence, administration of exogenous BDNF may delay or stop illness progression.

show abstract

Section: Methodsmentioning

confidence: 99%

“…Cresyl violet staining and immunohistochemistry assays were performed on paraformaldehyde fixed material as described previously (Canals et al, 2001). Animals were transcardially perfused with 4% paraformaldehyde solution in 0.1 M sodium phosphate, pH 7.2, at 15 d and 30 weeks of age.…”

Section: Methodsmentioning

confidence: 99%

Brain-Derived Neurotrophic Factor Regulates the Onset and Severity of Motor Dysfunction Associated with Enkephalinergic Neuronal Degeneration in Huntington's Disease

Canals¹,

Pineda²,

et al. 2004

View full text Add to dashboard Cite

show abstract

“…For examination of BDNF mRNA levels, we performed in situ hybridization with radioactive riboprobes, as described elsewhere (Canals et al 2001). An antisense cRNA probe to detect the transcripts of mouse BDNF was prepared by in vitro transcription using T7 RNA polymerase (Promega) and 33 P-UTP (Bioscience Europe).…”

Section: Dopamine Measurementsmentioning

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

Self Cite

View full text Add to dashboard Cite

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...

show abstract

“…8,9 Mutant huntingtin alters the BDNF function by an impairment in its transport, which results in deficient striatal BDNF levels. 10,11 Furthermore, mutant huntingtin also deregulates the BDNF transcription in the cerebral cortex which, in turn, affects striatal BDNF levels.…”

Section: Introductionmentioning

confidence: 99%

BDNF regulation under GFAP promoter provides engineered astrocytes as a new approach for long-term protection in Huntington's disease

et al. 2010

View full text Add to dashboard Cite

Brain-derived neurotrophic factor (BDNF) is the main candidate for neuroprotective therapeutic strategies for Huntington's disease. However, the administration system and the control over the dosage are still important problems to be solved. Here we generated transgenic mice overexpressing BDNF under the promoter of the glial fibrillary acidic protein (GFAP) (pGFAP-BDNF mice). These mice are viable and have a normal phenotype. However, intrastriatal administration of quinolinate increased the number of reactive astrocytes and enhanced the release of BDNF in pGFAP-BDNF mice compared with wild-type mice. Coincidentally, pGFAP-BDNF mice are more resistant to quinolinate than wild-type mice, suggesting a protective effect of astrocyte-derived BDNF. To verify this, we next cultured astrocytes from pGFAP-BDNF and wild-type mice for grafting. Wild-type and pGFAP-BDNF-derived astrocytes behave similarly in nonlesioned mice. However, pGFAP-BDNF-derived astrocytes showed higher levels of BDNF and larger neuroprotective effects than the wild-type ones when quinolinate was injected 30 days after grafting. Interestingly, mice grafted with pGFAP-BDNF astrocytes showed important and sustained behavioral improvements over time after quinolinate administration as compared with mice grafted with wild-type astrocytes. These findings show that astrocytes engineered to release BDNF can constitute a therapeutic approach for Huntington's disease.

show abstract

Expression of Brain-Derived Neurotrophic Factor in Cortical Neurons Is Regulated by Striatal Target Area

Cited by 98 publications

References 52 publications

Brain-Derived Neurotrophic Factor Regulates the Onset and Severity of Motor Dysfunction Associated with Enkephalinergic Neuronal Degeneration in Huntington's Disease

Brain-Derived Neurotrophic Factor Regulates the Onset and Severity of Motor Dysfunction Associated with Enkephalinergic Neuronal Degeneration in Huntington's Disease

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

BDNF regulation under GFAP promoter provides engineered astrocytes as a new approach for long-term protection in Huntington's disease

Contact Info

Product

Resources

About