Genetic Deletion of the Histone Deacetylase 6 Exacerbates Selected Behavioral Deficits in the R6/1 Mouse Model for Huntington's Disease

Overview

Journal Brain Behav

Specialty Psychology

Date 2015 Oct 8

PMID 26445700

Citations 5

Authors

Alienor Ragot

Susanna Pietropaolo

Jean Vincent

Pauline Delage

Hongyu Zhang

Bernadette Allinquant

Xavier Leinekugel

Andre Fischer

Yoon H Cho

Affiliations

Soon will be listed here.

Abstract

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.

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References

Graff J, Rei D, Guan J, Wang W, Seo J, Hennig K . An epigenetic blockade of cognitive functions in the neurodegenerating brain. Nature. 2012; 483(7388):222-6. PMC: 3498952. DOI: 10.1038/nature10849. View

Goodson J, Thompson R . Nonapeptide mechanisms of social cognition, behavior and species-specific social systems. Curr Opin Neurobiol. 2010; 20(6):784-94. DOI: 10.1016/j.conb.2010.08.020. View

Terranova M, Laviola G, Alleva E . Ontogeny of amicable social behavior in the mouse: gender differences and ongoing isolation outcomes. Dev Psychobiol. 1993; 26(8):467-81. DOI: 10.1002/dev.420260805. View

Paradiso S, Turner B, Paulsen J, Jorge R, Ponto L, Robinson R . Neural bases of dysphoria in early Huntington's disease. Psychiatry Res. 2007; 162(1):73-87. PMC: 3348657. DOI: 10.1016/j.pscychresns.2007.04.001. View

Lee J, Mahendran A, Yao Y, Ngo L, Venta-Perez G, Choy M . Development of a histone deacetylase 6 inhibitor and its biological effects. Proc Natl Acad Sci U S A. 2013; 110(39):15704-9. PMC: 3785767. DOI: 10.1073/pnas.1313893110. View

Bobrowska A, Paganetti P, Matthias P, Bates G . Hdac6 knock-out increases tubulin acetylation but does not modify disease progression in the R6/2 mouse model of Huntington's disease. PLoS One. 2011; 6(6):e20696. PMC: 3108987. DOI: 10.1371/journal.pone.0020696. View

Spires T, Grote H, Varshney N, Cordery P, Dellen A, Blakemore C . Environmental enrichment rescues protein deficits in a mouse model of Huntington's disease, indicating a possible disease mechanism. J Neurosci. 2004; 24(9):2270-6. PMC: 6730435. DOI: 10.1523/JNEUROSCI.1658-03.2004. View

Baquet Z, Gorski J, Jones K . Early striatal dendrite deficits followed by neuron loss with advanced age in the absence of anterograde cortical brain-derived neurotrophic factor. J Neurosci. 2004; 24(17):4250-8. PMC: 6729276. DOI: 10.1523/JNEUROSCI.3920-03.2004. View

Pietropaolo S, Delage P, Cayzac S, Crusio W, Cho Y . Sex-dependent changes in social behaviors in motor pre-symptomatic R6/1 mice. PLoS One. 2011; 6(5):e19965. PMC: 3095644. DOI: 10.1371/journal.pone.0019965. View

10.

Lebreton F, Cayzac S, Pietropaolo S, Jeantet Y, Cho Y . Sleep Physiology Alterations Precede Plethoric Phenotypic Changes in R6/1 Huntington's Disease Mice. PLoS One. 2015; 10(5):e0126972. PMC: 4428700. DOI: 10.1371/journal.pone.0126972. View

11.

Dompierre J, Godin J, Charrin B, Cordelieres F, King S, Humbert S . Histone deacetylase 6 inhibition compensates for the transport deficit in Huntington's disease by increasing tubulin acetylation. J Neurosci. 2007; 27(13):3571-83. PMC: 6672116. DOI: 10.1523/JNEUROSCI.0037-07.2007. View

12.

Deacon R, Rawlins J . Hippocampal lesions, species-typical behaviours and anxiety in mice. Behav Brain Res. 2004; 156(2):241-9. DOI: 10.1016/j.bbr.2004.05.027. View

13.

Iwata A, Riley B, Johnston J, Kopito R . HDAC6 and microtubules are required for autophagic degradation of aggregated huntingtin. J Biol Chem. 2005; 280(48):40282-92. DOI: 10.1074/jbc.M508786200. View

14.

de Ruijter A, van Gennip A, Caron H, Kemp S, van Kuilenburg A . Histone deacetylases (HDACs): characterization of the classical HDAC family. Biochem J. 2002; 370(Pt 3):737-49. PMC: 1223209. DOI: 10.1042/BJ20021321. View

15.

Nithianantharajah J, Barkus C, Murphy M, Hannan A . Gene-environment interactions modulating cognitive function and molecular correlates of synaptic plasticity in Huntington's disease transgenic mice. Neurobiol Dis. 2008; 29(3):490-504. DOI: 10.1016/j.nbd.2007.11.006. View

16.

Lawrence A, Hodges J, Rosser A, Kershaw A, Ffrench-Constant C, Rubinsztein D . Evidence for specific cognitive deficits in preclinical Huntington's disease. Brain. 1998; 121 ( Pt 7):1329-41. DOI: 10.1093/brain/121.7.1329. View

17.

Craufurd D, Thompson J, Snowden J . Behavioral changes in Huntington Disease. Neuropsychiatry Neuropsychol Behav Neurol. 2001; 14(4):219-26. View

18.

Peng Q, Masuda N, Jiang M, Li Q, Zhao M, Ross C . The antidepressant sertraline improves the phenotype, promotes neurogenesis and increases BDNF levels in the R6/2 Huntington's disease mouse model. Exp Neurol. 2007; 210(1):154-63. PMC: 2278120. DOI: 10.1016/j.expneurol.2007.10.015. View

19.

Tabrizi S, Langbehn D, Leavitt B, Roos R, Durr A, Craufurd D . Biological and clinical manifestations of Huntington's disease in the longitudinal TRACK-HD study: cross-sectional analysis of baseline data. Lancet Neurol. 2009; 8(9):791-801. PMC: 3725974. DOI: 10.1016/S1474-4422(09)70170-X. View

20.

Pang T, Stam N, Nithianantharajah J, Howard M, Hannan A . Differential effects of voluntary physical exercise on behavioral and brain-derived neurotrophic factor expression deficits in Huntington's disease transgenic mice. Neuroscience. 2006; 141(2):569-584. DOI: 10.1016/j.neuroscience.2006.04.013. View