Rescue of histone hypoacetylation and social deficits by ketogenic diet in a Shank3 mouse model of autism

Neuropsychopharmacology. 2022 May;47(6):1271-1279. doi: 10.1038/s41386-021-01212-1. Epub 2021 Oct 26.


Human genetic sequencing has implicated epigenetic and synaptic aberrations as the most prominent risk factors for autism. Here we show that autistic patients exhibit the significantly lower histone acetylation and elevated HDAC2 expression in prefrontal cortex (PFC). The diminished histone acetylation is also recaptured in an autism mouse model with the deficiency of the Shank3 gene encoding a synaptic scaffolding protein. Treating young (5-week-old) Shank3-deficient mice with a 4-week ketogenic diet, which can act as an endogenous inhibitor of class I HDACs via the major product β-hydroxybutyrate, elevates the level of histone acetylation in PFC neurons. Behavioral assays indicate that ketogenic diet treatment leads to the prolonged rescue of social preference deficits in Shank3-deficient mice. The HDAC downstream target genes encoding NMDA receptor subunits, GRIN2A and GRIN2B, are significantly reduced in PFC of autistic humans. Ketogenic diet treatment of Shank3-deficient mice elevates the transcription and histone acetylation of Grin2a and Grin2b, and restores the diminished NMDAR synaptic function in PFC neurons. These results suggest that the ketogenic diet provides a promising therapeutic strategy for social deficits in autism via the restoration of histone acetylation and gene expression in the brain.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autistic Disorder*
  • Diet, Ketogenic*
  • Disease Models, Animal
  • Histone Deacetylases / metabolism
  • Histones / metabolism
  • Humans
  • Mice
  • Microfilament Proteins / metabolism
  • Microfilament Proteins / therapeutic use
  • Nerve Tissue Proteins / metabolism
  • Receptors, N-Methyl-D-Aspartate


  • Histones
  • Microfilament Proteins
  • Nerve Tissue Proteins
  • Receptors, N-Methyl-D-Aspartate
  • SHANK3 protein, human
  • Shank3 protein, mouse
  • Histone Deacetylases