A ketogenic diet rescues hippocampal memory defects in a mouse model of Kabuki syndrome

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.

Exogenous and endogenous HDAC inhibitor effects in Rubinstein-Taybi syndrome models

“…This data is extremely relevant, considering that butyrate acts as endogenous HDACi (Davie, 2003) and further study should be aimed to elucidate this possible genetic-microbial additive negative effect. A recent study reported the effects of a ketogenic diet in a mouse model of Kabuki syndrome (Benjamin et al, 2017). Kabuki syndrome (OMIM# 147920, # 300867) is a rare genetic syndrome that overlaps Rubinstein-Taybi syndrome both at the clinical and genetic levels.…”

“…Patients share many clinical signs and, at the molecular level, both syndromes are due to defects in the epigenetic machinery, mainly involving the histone modification level. In the Kabuki mouse model, ketogenic diet induces the endogenous production of deacetylase inhibitors that normalizes the overall state of histone modification and determines an improvement of clinical conditions (Benjamin et al, 2017). Ketogenic diet, having an unbalanced macronutrient composition, highly impacts on both microbiota composition and metabolism (Lindefeldt et al, 2019).…”

Precocious Chondrocyte Differentiation Disrupts Skeletal Growth in Kabuki Syndrome Mice

“…Kmt2d +/bGeo mice have been previously described (15,16). Mice were housed in a clean, specific pathogen-free state-of-the-art animal facility in ventilated racks and provided ad lib access to a standard rodent diet and to filtered water via an automatic watering system.…”

“…Kmt2d +/bGeo mice have disrupted H3K4 trimethylation (H3K4me3) in the dentate gyrus of the hippocampus and associated neurogenesis defects and memory deficits. All three features could be reversed by postnatal administration of agents that favor chromatin opening such as HDAC inhibitors or the HDAC inhibitor-like ketone body, betahydroxybutyrate (15,16). Kmt2d +/bGeo mice also weigh less than Kmt2d +/+ littermates and exhibit a flattened facial profile like individuals with KS1 (15).…”

Iron and restless legs syndrome: treatment, genetics and pathophysiology

“…Haploinsufficiency of KDM6A is a cause of mental retardation in Kabuki syndrome (MIM 147920). Interestingly, the preponderance of open chromatin marks in Kabuki syndrome appears to be amenable to inhibitors of histone deacetylation [102] such as β-hydroxybutyrate generated by ketogenic diet [103]. …”