HDAC inhibitor ameliorates behavioral deficits in Mecp2308/y mouse model of Rett syndrome

Nicolas Lebrun; Chloé Delépine; Mohamed Selloum; Hamid Meziane; Juliette Nectoux; Yann Herault; Thierry Bienvenu

doi:10.1016/j.brainres.2021.147670

HDAC inhibitor ameliorates behavioral deficits in Mecp2^308/y mouse model of Rett syndrome

Brain Res. 2021 Dec 1:1772:147670. doi: 10.1016/j.brainres.2021.147670. Epub 2021 Sep 25.

Authors

Nicolas Lebrun¹, Chloé Delépine², Mohamed Selloum³, Hamid Meziane³, Juliette Nectoux⁴, Yann Herault³, Thierry Bienvenu⁵

Affiliations

¹ INSERM U1266, Institut de Psychiatrie et de Neurosciences de Paris (IPNP), Paris, France.
² INSERM, U1016, Institut Cochin, Paris, France; CNRS, UMR8104, Paris, France; Université de Paris, France; Massachusetts Institute of Technology, Department of Brain and Cognitive Sciences, Picower Institute for Learning and Memory, Cambridge, MA, USA.
³ Celphedia, PHENOMIN, Institut Clinique de la Souris (ICS), GIE CERBM, Illkirch, France; Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France; Centre National de la Recherche Scientifique, UMR7104, Illkirch, France; Institut National de la Santé et de la Recherche Médicale, U964 Illkirch, France; Université de Strasbourg, Illkirch, France.
⁴ Laboratoire de Génétique et de Biologie Moléculaires, APHP. Centre Université de Paris, France.
⁵ INSERM U1266, Institut de Psychiatrie et de Neurosciences de Paris (IPNP), Paris, France; Université de Paris, France; Laboratoire de Génétique et de Biologie Moléculaires, APHP. Centre Université de Paris, France. Electronic address: thierry.bienvenu@inserm.fr.

PMID: 34582789
DOI: 10.1016/j.brainres.2021.147670

Abstract

Rett syndrome (RTT) is a rare X-linked neurodevelopmental disorder. More than 95% of classic RETT syndrome cases result from pathogenic variants in the methyl-CpG binding protein 2 (MECP2) gene. Nevertheless, it has been established that a spectrum of neuropsychiatric phenotypes is associated with MECP2 variants in both females and males. We previously reported that microtubule growth velocity and vesicle transport directionality are altered in Mecp2-deficient astrocytes from newborn Mecp2-deficient mice compared to that of their wild-type littermates suggesting deficit in microtubule dynamics. In this study, we report that administration of tubastatin A, a selective HDAC6 inhibitor, restored microtubule dynamics in Mecp2-deficient astrocytes. We furthermore report that daily doses of tubastatin A reversed early impaired exploratory behavior in male Mecp2^308/y mice. These findings are a first step toward the validation of a novel treatment for RTT.

Keywords: Astrocytes; HDAC6; MeCP2; Microtubules; Rett syndrome; Tubastatin A.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Astrocytes / metabolism
Behavior, Animal*
Exploratory Behavior
Female
Histone Deacetylase 6 / antagonists & inhibitors*
Histone Deacetylase Inhibitors / pharmacology
Histone Deacetylase Inhibitors / therapeutic use*
Hydroxamic Acids / therapeutic use
Indoles / therapeutic use
Male
Methyl-CpG-Binding Protein 2 / genetics*
Mice
Mice, Inbred C57BL
Mice, Knockout
Microtubules / drug effects
Psychomotor Performance / drug effects
Rett Syndrome / drug therapy*
Rett Syndrome / psychology*
Social Behavior

Substances

Histone Deacetylase Inhibitors
Hydroxamic Acids
Indoles
Mecp2 protein, mouse
Methyl-CpG-Binding Protein 2
tubastatin A
Hdac6 protein, mouse
Histone Deacetylase 6