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

• Main Authors: Lao-Peregrin Cristina, Carretón Olga, Giralt Albert, Martín Eduardo D, Alberch Jordi
• Format: Article
• Language: English
• Published: BMC 2011-10-01
• Series: Molecular Neurodegeneration
• Subjects: Huntingtin; synaptic plasticity; therapy; astrocytes; learning; Long-term potentiation
• Online Access: http://www.molecularneurodegeneration.com/content/6/1/71

<p>Abstract</p> <p>Background</p> <p>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.</p> <p>Results</p> <p>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.</p> <p>Conclusions</p> <p>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.</p>