Genetic deletion of the Histone Deacetylase 6 exacerbates selected behavioral deficits in the R6/1 mouse model for Huntington's disease

Brain Behav. 2015 Sep;5(9):e00361. doi: 10.1002/brb3.361. Epub 2015 Jun 24.


Introduction: The inhibition of the Histone Deacetylase 6 (HDAC6) increases tubulin acetylation, thus stimulating intracellular vesicle trafficking and brain-derived neurotrophic factor (BDNF) release, that is, cellular processes markedly reduced in Huntington's disease (HD).

Methods: We therefore tested that reducing HDAC6 levels by genetic manipulation would attenuate early cognitive and behavioral deficits in R6/1 mice, a mouse model which develops progressive HD-related phenotypes.

Results: In contrast to our initial hypothesis, the genetic deletion of HDAC6 did not reduce the weight loss or the deficits in cognitive abilities and nest-building behavior shown by R6/1 mice, and even worsened their social impairments, hypolocomotion in the Y-maze, and reduced ultrasonic vocalizations.

Conclusions: These results weaken the validity of HDAC6 reduction as a possible therapeutic strategy for HD. The data are discussed in terms of additional cellular consequences and anatomical specificity of HDAC6 that could explain these unexpected effects.

Keywords: Brain-derived neurotrophic factor; cognitive behavior; epigenetics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Animals
  • Behavior, Animal / physiology
  • Brain / enzymology
  • Brain / metabolism
  • Brain / physiology
  • Brain-Derived Neurotrophic Factor / metabolism
  • Cognition / physiology
  • Disease Models, Animal
  • Gene Deletion
  • Histone Deacetylase 6
  • Histone Deacetylases / genetics*
  • Histone Deacetylases / metabolism
  • Huntington Disease / enzymology*
  • Huntington Disease / genetics*
  • Huntington Disease / therapy
  • Male
  • Mice
  • Mice, Transgenic
  • Motor Activity / physiology
  • Tubulin / genetics
  • Tubulin / metabolism


  • Brain-Derived Neurotrophic Factor
  • Tubulin
  • Hdac6 protein, mouse
  • Histone Deacetylase 6
  • Histone Deacetylases