A Ketogenic Diet Rescues Hippocampal Memory Defects in a Mouse Model of Kabuki Syndrome

Proc Natl Acad Sci U S A. 2017 Jan 3;114(1):125-130. doi: 10.1073/pnas.1611431114. Epub 2016 Dec 20.

Abstract

Kabuki syndrome is a Mendelian intellectual disability syndrome caused by mutations in either of two genes (KMT2D and KDM6A) involved in chromatin accessibility. We previously showed that an agent that promotes chromatin opening, the histone deacetylase inhibitor (HDACi) AR-42, ameliorates the deficiency of adult neurogenesis in the granule cell layer of the dentate gyrus and rescues hippocampal memory defects in a mouse model of Kabuki syndrome (Kmt2d+/βGeo). Unlike a drug, a dietary intervention could be quickly transitioned to the clinic. Therefore, we have explored whether treatment with a ketogenic diet could lead to a similar rescue through increased amounts of beta-hydroxybutyrate, an endogenous HDACi. Here, we report that a ketogenic diet in Kmt2d+/βGeo mice modulates H3ac and H3K4me3 in the granule cell layer, with concomitant rescue of both the neurogenesis defect and hippocampal memory abnormalities seen in Kmt2d+/βGeo mice; similar effects on neurogenesis were observed on exogenous administration of beta-hydroxybutyrate. These data suggest that dietary modulation of epigenetic modifications through elevation of beta-hydroxybutyrate may provide a feasible strategy to treat the intellectual disability seen in Kabuki syndrome and related disorders.

Keywords: adult neurogenesis; epigenetics; histone machinery; intellectual disability; ketone bodies.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 3-Hydroxybutyric Acid / metabolism
  • Abnormalities, Multiple / diet therapy*
  • Abnormalities, Multiple / genetics
  • Animals
  • Diet, Ketogenic / methods*
  • Disease Models, Animal
  • Face / abnormalities*
  • Hematologic Diseases / diet therapy*
  • Hematologic Diseases / genetics
  • Hippocampus / cytology
  • Hippocampus / metabolism*
  • Histone Demethylases / genetics
  • Histone-Lysine N-Methyltransferase / genetics
  • Histones / biosynthesis*
  • Intellectual Disability / diet therapy*
  • Intellectual Disability / genetics
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Myeloid-Lymphoid Leukemia Protein / genetics
  • Neurogenesis / genetics
  • Neurogenesis / physiology*
  • Vestibular Diseases / diet therapy*
  • Vestibular Diseases / genetics

Substances

  • Histones
  • Myeloid-Lymphoid Leukemia Protein
  • Histone Demethylases
  • Utx protein, mouse
  • Histone-Lysine N-Methyltransferase
  • Kmt2b protein, mouse
  • 3-Hydroxybutyric Acid

Supplementary concepts

  • Kabuki syndrome