Modulation of Phospho-CREB by Systemically Administered Recombinant BDNF in the Hippocampus of the R6/2 Mouse Model of Huntington's Disease.

ABSTRACT

Huntington's disease (HD) is an autosomal dominant neurodegenerative disease due to an expansion of a trinucleotide repeats in IT15 gene encoding for the protein huntingtin. Motor dysfunction, cognitive decline, and psychiatric disorder are typical clinical signs of HD. In HD, mutated huntingtin causes a major loss of brain derived neurotrophic factor (BDNF), causing striatal atrophy. Moreover, a key involvement of BDNF was observed in the synaptic plasticity that controls the acquisition and/or consolidation of certain forms of memory. We studied changes in hippocampal BDNF and in CREB in the R6/2 mouse model of HD. Moreover, we investigated if the beneficial effects of systemically administered recombinant BDNF observed in the striatum and cortex had an effect also on the hippocampus. Osmotic minipumps that chronically released recombinant BDNF or saline solution from 4 weeks of age until euthanasia were implanted into R6/2 and wild type mice. Our data show that BDNF is severely decreased in the hippocampus of R6/2 mice, while BDNF treatment restored its physiological levels. Moreover, the chronic administration of recombinant BDNF promoted the increment of phosphorylated CREB protein. Our study demonstrates the involvement of hippocampus in the pathology of R6/2 model of HD and correlates the beneficial effects of BDNF administration with increased hippocampal levels of BDNF and pCREB.