Journal
MOLECULAR NEURODEGENERATION
Volume 6, Issue -, Pages -Publisher
BIOMED CENTRAL LTD
DOI: 10.1186/1750-1326-6-71
Keywords
Huntingtin; synaptic plasticity; therapy; astrocytes; learning; Long-term potentiation
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Funding
- Confocal Microscopy Facility (Campus Casanova) of the Centre Cientific i Tecnologic (Universitat de Barcelona)
- Ministerio de Ciencia e Innovacion [SAF2008-04360, BFU2008-04196/BFI]
- INCRECyT
- Instituto de Salud Carlos III: CIBERNED
- Red de Terapia Celular [RD06/0010/0006]
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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.
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