Research article

Conditional BDNF release under pathological conditions improves Huntington's disease pathology by delaying neuronal dysfunction

Albert Giralt^1,2,3, Olga Carretón^1,2,3, Cristina Lao-Peregrin⁴, Eduardo D Martín⁴ and Jordi Alberch^1,2,3*

• * Corresponding author: Jordi Alberch alberch@ub.edu

Author Affiliations

¹ Departament de Biologia Cel•lular, Immunologia i Neurociències, Facultat de Medicina, Universitat de Barcelona, Barcelona, Spain

² Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Casanova 143, Barcelona, Spain

³ Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain

⁴ Laboratory of Neurophysiology and Synaptic Plasticity, Albacete Science and Technology Park (PCYTA). Institute for Research in Neurological Disabilities (IDINE), University of Castilla-La Mancha, Albacete, Spain

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Molecular Neurodegeneration 2011, 6:71 doi:10.1186/1750-1326-6-71

Published: 10 October 2011

Abstract

Background

Brain-Derived Neurotrophic Factor (BDNF) is the main candidate for neuroprotective therapy for Huntington's disease (HD), but its conditional administration is one of its most challenging problems.

Results

Here we used transgenic mice that over-express BDNF under the control of the Glial Fibrillary Acidic Protein (GFAP) promoter (pGFAP-BDNF mice) to test whether up-regulation and release of BDNF, dependent on astrogliosis, could be protective in HD. Thus, we cross-mated pGFAP-BDNF mice with R6/2 mice to generate a double-mutant mouse with mutant huntingtin protein and with a conditional over-expression of BDNF, only under pathological conditions. In these R6/2:pGFAP-BDNF animals, the decrease in striatal BDNF levels induced by mutant huntingtin was prevented in comparison to R6/2 animals at 12 weeks of age. The recovery of the neurotrophin levels in R6/2:pGFAP-BDNF mice correlated with an improvement in several motor coordination tasks and with a significant delay in anxiety and clasping alterations. Therefore, we next examined a possible improvement in cortico-striatal connectivity in R62:pGFAP-BDNF mice. Interestingly, we found that the over-expression of BDNF prevented the decrease of cortico-striatal presynaptic (VGLUT1) and postsynaptic (PSD-95) markers in the R6/2:pGFAP-BDNF striatum. Electrophysiological studies also showed that basal synaptic transmission and synaptic fatigue both improved in R6/2:pGAP-BDNF mice.

Conclusions

These results indicate that the conditional administration of BDNF under the GFAP promoter could become a therapeutic strategy for HD due to its positive effects on synaptic plasticity.